Octa-aminopropyl polyhedral oligomeric silsesquioxane-functionalized magnetic dextran nanoparticles via dynamic Schiff-base imine bonds for sustained doxorubicin release

Octa-aminopropyl polyhedral oligomeric silsesquioxane-functionalized magnetic dextran nanoparticles via dynamic Schiff-base imine bonds for sustained doxorubicin release | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Octa-aminopropyl polyhedral oligomeric silsesquioxane-functionalized magnetic dextran nanoparticles via dynamic Schiff-base imine bonds for sustained doxorubicin release Ramezan Ali Taheri, Ali Mohammadzadeh, Reza Mohammadi, Mohammad Reza Khodabakhshi, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9419286/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 10 You are reading this latest preprint version Abstract In this study, a pH-responsive drug delivery system (DDS) based on octa-aminopropyl polyhedral oligomeric silsesquioxane (OA-POSS), dextran (Dex), and magnetic nanoparticles (MNPs) was developed for potential cancer therapy applications. Fe 3 O 4 NPs were initially synthesized and subsequently functionalized with dextran dialdehyde (Dex-DA) and OA-POSS through a Schiff-base imine reaction, yielding the Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS nanocarrier (NC). Doxorubicin (DOX), used as a model anticancer agent, was successfully loaded onto the NC via noncovalent physical interactions, achieving a high drug loading efficiency of approximately 95%. The synthesized NCs were characterized using FT-IR, FE-SEM, DLS, XRD, and VSM techniques. In vitro drug release studies demonstrated pronounced pH-responsive behavior. At physiological pH (7.4), less than 15% of DOX was released, whereas under acidic conditions (pH 5), approximately 81% of the drug was released over a period 6 days. Cytotoxicity assessments revealed that the blank Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS NCs were biocompatible with cell viability above 85%. In contrast, DOX-loaded NCs exhibited strong anticancer activity against A549 cells, with an IC 50 value of around 1 µg/mL, attributed to the controlled release of DOX. Overall, the Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS/DOX NC shows promising potential as a targeted and stimuli-responsive drug delivery platform for cancer treatment. Octa-aminopropyl polyhedral oligomeric silsesquioxane Schiff-base imine reaction Dextran dialdehyde pH-sensitive system Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1. Introduction Doxorubicin (DOX) is an effective anticancer agent that induces cell death by interfering with DNA function and inhibiting cellular proliferation (Mohammadzadeh et al. 2025 ; Hongliu Yu et al. 2024 ). However, its therapeutic application is limited by poor selectivity, as it also damages healthy cells, leading to severe side effects such as cardiotoxicity (Linders et al. 2024 ; Qiong Wang et al. 2024 ). This challenge is particularly evident in diseases like lung cancer, one of the most common and deadly cancer types, where DOX can effectively suppress tumor cell growth, but its systemic toxicity restricts optimal dosing. To overcome these drawbacks, advanced targeted drug delivery systems (DDSs) have been developed (van der Merwe et al. 2025 ). In these systems, the drug is encapsulated within nanoscale carriers designed to deliver it directly and in a controlled manner to tumor tissues (Tenchov et al. 2025 ). This strategy enhances drug accumulation at the tumor site while minimizing harm to normal tissues and reducing systemic toxicity (Hosseinzadeh et al. 2025 ; Beilei Liu et al. 2024a ). Nanoparticles (NPs), a subset of nanoscale drug carriers, are important in targeted drug delivery due to their ability to cross biological barriers and selectively accumulate in tumors via the enhanced permeability and retention )EPR( effect (Long et al. 2023 ; Vagena et al. 2025 ). Fe 3 O 4 magnetite NPs (MNPs) are particularly attractive because of their superparamagnetic behavior, biocompatibility, and low toxicity (Foroutan et al. 2025a ). They can be guided by an external magnetic field and serve both as drug carriers and magnetic resonance imaging (MRI) contrast agents for theranostic applications (Ngwu-Hyacinth et al. 2025 ). Bare MNPs exhibit pronounced chemical reactivity and are prone to oxidation, which may compromise their magnetic properties (Ghasemi et al. 2025 ). Consequently, it is essential to develop strategies that enhance their chemical stability, biodegradability, and in vivo compatibility. Surface modification has emerged as a crucial approach to improve the performance of MNPs as drug carriers (Rahimkhoei et al. 2024 ). Although Fe 3 O 4 MNPs inherently possess a hydrophobic surface, clinical applications require them to be rendered hydrophilic and biocompatible. Surface coatings not only prevent particle aggregation but also enhance overall stability (Yingjie Yu et al. 2019 ). Common modifications include SiO 2 , organic molecules, proteins, and polymers (Zhou et al. 2025 ). In particular, polymeric coatings facilitate the generation of hydrophilic nanostructures and present reactive functional groups that enhance drug conjugation efficiency while concurrently mitigating NP aggregation (Beach et al. 2024 ). The incorporation of magnetic nanoparticles (MNPs) into polymer-based composites has unlocked new avenues in diverse fields, including biomedical engineering, tissue engineering, drug delivery systems (DDSs), as well as packaging and food processing, highlighting their versatile functional potential (Sharifianjazi et al. 2021 ; Zefeng Wang et al. 2022b ). The selection of an appropriate polymer necessitates a comprehensive understanding of both its surface and bulk properties, as these intrinsic characteristics critically govern its functional performance (Venkataraman et al. 2011 ). In drug delivery applications, both synthetic and natural polymers are utilized; however, natural polymers are often preferred due to their renewable sources, chemical versatility, biodegradability, and cost-effectiveness (Bijudas et al. 2025 ; Prasad et al. 2023 ). Common examples include chitosan, albumin, alginate, collagen, gelatin, and dextran (Shaikh et al. 2022 ). Dextran (Dex), a natural polysaccharide composed of D-glucose units, is mainly produced by Leuconostoc mesenteroides through fermentation (Zuo et al. 2024 ). Its backbone consists primarily of α-(1→6) glycosidic linkages, with side branches connected via α-(1→3) or α-(1→4) bonds (Yang et al. 2022 ). This branched architecture imparts high water solubility, enabling efficient drug encapsulation and transport (Yifan Liu et al. 2024b ). Moreover, the abundance of functional groups in dextran allows for facile chemical modification and conjugation with ligands or nanoparticles, while also enhancing drug circulation time and targeted delivery to specific tissues (Petrovici et al. 2023 ; Ramasundaram et al. 2022 ). Octa-amino propyl polyhedral oligomeric silsesquioxane (OA-POSS) represents a class of hybrid inorganic–organic nanostructures consisting of a silica-like (Si–O–Si) cage functionalized with tunable organic substituents (Liang et al. 2024 ; Loman-Cortes et al. 2021 ). Due to its highly ordered cage-like architecture, OA-POSS functions as a multifunctional nanomolecular platform enabling efficient drug encapsulation, protection, and controlled release (Chang et al. 2024 ). Fe 3 O 4 MNPs coated with natural polymers, despite their numerous advantages, also exhibit certain drawbacks such as immune system activation and inflammation, accumulation in organs, nonspecific binding, and irregular drug degradation and release within the body (Nordin et al. 2023 ). These limitations can be effectively mitigated through surface modification with OA-POSS (Shang et al. 2025 ). The primary aim of this study is to design and fabricate core–shell drug bio-nanocomposites engineered to respond to pH variations and externally applied magnetic fields, enabling controlled and targeted therapeutic delivery. Initially, Fe 3 O 4 @SiO 2 @Dex nanocomposites were synthesized, and the Dex coating on the Fe 3 O 4 surface was subsequently oxidized to its dialdehyde form (Dex-DA) using sodium periodate. To enhance drug-loading capacity and achieve a more controlled release behavior, the surface of Fe 3 O 4 @ SiO 2 @Dex-DA was further functionalized with OA-POSS by means of a reversible Schiff-base condensation reaction. Subsequently, the anticancer drug DOX was loaded onto the Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS bio-nanocomposite via hydrogen bonding and electrostatic interactions. The drug release profile, release kinetics, and in vitro cytotoxicity (MTT assay) were systematically evaluated. It is proposed that the imine bonds incorporated within the NC, owing to their stability at physiological pH and selective cleavage under mildly acidic conditions, can effectively mitigate the initial burst release and substantially extend the drug release profile. Overall, the obtained results suggest that Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS/DOX can serve as an efficient and stimuli-responsive DDS for potential cancer therapy applications. 2. Experimental section 2.1. Materials and chemicals Dextran (Dex, average molecular weight 500,000 Da, relative viscosity 25–40%, 1% solution in H 2 O at 25°C, purity ≥ 99.0% (was purchased from Nippon Sourced Paper Chemicals (Japan). Iron (III) chloride hexahydrate (FeCl 3 .6H 2 O, 98% Purity, Sigma Aldrich), Iron (II) chloride tetrahydrate (FeCl 2 ·4H 2 O, 98% Purity, Sigma Aldrich), Sodium periodate (NaIO 4 , 99% Purity, Sigma Aldrich), 3-aminopropyl trimethoxy silane (APTES, 97% Purity, Sigma Aldrich), Ammonium hydroxide (NH 4 OH, 25% w/w, Sigma Aldrich), Methanol (CH 3 OH, ≥ 99.8% Purity, Sigma Aldrich), Hydrochloric acid (HCl, 37% w/w, Sigma Aldrich), Ethylene glycol (C 2 H 6 O 2 , ≥ 99% Purity, Sigma Aldrich), Ethanol (C 2 H 5 OH, ≥ 99.8% Purity, Sigma Aldrich), Buffers: sodium acetate buffer (SAB, pH 5), phosphate-buffered saline (PBS, pH 7.4), and deionized water (H 2 O) were utilized throughout the study. The deionized water was freshly prepared in the laboratory prior to use. All other chemicals were obtained from Merck and used as received without any further purification. Doxorubicin hydrochloride (DOX) was sourced from Sobhan Pharmaceuticals Co. (Iran) and utilized directly in its supplied form, without undergoing any additional purification or modification. 2.2. Physical Characterization Ultraviolet visible (UV–Vis) absorption spectra of the samples were measured using a Shimadzu UV-1700 spectrophotometer to assess their optical properties. Fourier transform infrared (FT-IR) spectra were recorded at 25°C on a Bruker Aquinox 55 spectrometer, covering the spectral range from 400 to 4000 cm − 1 . The magnetic characteristics of the core–shell magnetic nanoparticles were evaluated with a Lakeshore Model 7410 vibrating sample magnetometer (VSM). Structural analysis was carried out through X-ray diffraction (XRD) using a Bruker D8 diffractometer, with scans performed in the 2θ range of 10°–70°. The surface morphology of the NPs was examined via scanning electron microscopy (SEM) using a TESCAN MIRA instrument (working distance: 3.22 mm, field of view: 2.54 µm, magnification: 50,000×). Elemental composition was assessed by energy-dispersive X-ray spectroscopy (EDX). Additionally, the hydrodynamic size distribution and zeta potential of the synthesized NPs were determined using dynamic light scattering (DLS) measurements (Malvern Instruments). 2.3. Preparation of Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS 2.3.1. Synthesis of Fe 3 O 4 @SiO 2 Fe 3 O 4 @SiO 2 MNPs were synthesized via a modified co-precipitation and Stöber process. Under a nitrogen atmosphere, FeCl 2 ·4H 2 O (3.96 g, 20 mmol) and FeCl 3 ·6H 2 O (10.82 g, 40 mmol) were dissolved in 320 mL of deionized water, followed by the slow addition of 40 mL NH 4 OH (25%) and stirring at 60°C for 8 h to yield Fe 3 O 4 NPs, which were magnetically separated and washed thoroughly. Subsequently, 2 g of Fe 3 O 4 was dispersed in an ethanol/deionized water mixture (160 mL: 24 mL), and 4 mL of NH 4 OH (25%) and 4 mL of TEOS were added. The mixture was stirred at room temperature (25°C) for 12 h, and the obtained Fe 3 O 4 @SiO 2 NPs were collected magnetically, washed with deionized water, and dried for further use (Mohammadzadeh et al. 2024b ). 2.3.2. Synthesis of Fe 3 O 4 @SiO 2 @Dex-DA For the synthesis of Fe 3 O 4 @SiO 2 @Dex-DA NPs, initially, 50 mg of Fe 3 O 4 @SiO 2 NPs were dispersed in 20 mL of deionized water by ultrasonication for 10 min to ensure a uniform suspension. Subsequently, 100 mg of dextran was added, and the suspension was gently stirred at 25°C for 12 h to achieve uniform coating of the polymer onto the NP surface. The resulting Fe 3 O 4 @SiO 2 @Dextran NPs were separated using an external magnetic field and rinsed thrice with deionized water to remove residual, unbound dextran. For oxidation, the dextran-coated NPs were redispersed in 10 mL of acetate buffer (0.1 M, pH 5.0), and 10 mL of freshly prepared sodium periodate solution (10 mM, ≈ 21 mg NaIO 4 ) was added dropwise under gentle stirring. The reaction was carried out in the dark at 4°C for 1 h to convert vicinal diols to dialdehyde groups. To quench residual periodate, 100 µL of ethylene glycol was added, and the mixture was stirred for 15 min. Dialdehyde-modified NPs were subsequently magnetically separated, thoroughly rinsed with deionized water, and preserved at 4°C (Guo et al. 2021 ; Shokri et al. 2022 ). 2.3.3. Synthesis of OA-POSS OA-POSS was prepared through the hydrolytic condensation of APTES under acidic conditions, as illustrated in Scheme 1 . In summary, methanol (180 mL) and concentrated hydrochloric acid (15 mL, 35–37%) were introduced into a 500 mL two-neck round-bottom flask equipped with a reflux condenser and a magnetic stirrer. APTES (7.5 mL, 30 mmol) was then added dropwise to the mixture at 60°C under continuous stirring. After complete addition, the reaction temperature was raised to 90°C, and the mixture was refluxed for 16 h. The resulting solution was cooled to 25°C and added dropwise into THF, leading to the formation of a white OA-POSS precipitate. The precipitate was collected, washed several times with THF, and dried under vacuum at 40°C for 24 h (Arsalani et al. 2019 ). 2.3.4. Synthesis of Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS NPs were obtained by forming a Schiff-base imine reaction between the aldehyde groups present on Fe 3 O 4 @SiO 2 @Dex-DA and the primary amine groups of OA-POSS. To begin, 0.2 g of Fe 3 O 4 @SiO 2 @Dex-DA was dispersed in 10 mL of distilled water under continuous mechanical stirring to obtain a homogeneous and stable colloidal suspension. In a separate container, 0.6 g of OA-POSS was dissolved in 15 mL of distilled water. The OA-POSS solution was then slowly added to the Fe 3 O 4 @SiO 2 @Dex-DA suspension, after which the pH of the reaction mixture was adjusted to approximately 7.4. The mixture was stirred at 25°C for 2 h, enabling the covalent attachment of OA-POSS to the NP surface. Finally, the modified NPs were collected using an external magnetic field, thoroughly washed with distilled water to remove any unattached components, and dried under vacuum at 25°C to obtain a clean and stable solid product (Mohammadzadeh et al. 2024a ). 2.3.5. DOX loading in Fe 3 O 4 @SiO 2 @Dex and Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS For DOX loading, 100 mg of Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS and Fe 3 O 4 @SiO 2 @Dex-DA were each mixed with 10 mg of DOX (2 mg/mL) in PBS (pH 7.4) and gently stirred for 30 min to obtain uniform suspensions. The mixtures were then incubated at 25°C with mild agitation in the dark for 72 h to ensure effective incorporation of DOX into the nanocarrier matrices. After the loading process, the DOX loaded NCs were separated using an external magnetic field and thoroughly washed with PBS (pH 7.4) to remove any unbound DOX. The purified nanocarriers were air-dried at 25°C. The concentration of unencapsulated DOX in the supernatants was measured utilizing UV–Vis spectrophotometry at 480 nm, and the drug loading efficiency (DLE) and drug encapsulation efficiency (DEE) were calculated using Equations (1) and (2) (Javanbakht and Mohammadi 2025 ; Sanson et al. 2010 ). $$\:DEE\left(\%\right)=\:\frac{Mass\:of\:DOX\:incorporated\:into\:the\:nanocarriers}{Mass\:of\:DOX\:added\:to\:the\:systems\:at\:the\:beginning}\times\:100\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\left(1\right)$$ $$\:DLE\left(\%\right)=\frac{Mass\:of\:DOX\:incorporated\:into\:the\:nanocarriers}{Total\:mass\:of\:the\:DOX-loaded\:nanocarriers}\times\:100\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\left(2\right)$$ 2.4. In vitro DOX release To assess the DOX release behavior, 10 mg of the DOX-loaded nanocarriers (Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS) were suspended in 10 mL of PBS and SAB, respectively. The samples were incubated at 37°C under gentle shaking. At predetermined time intervals, 2 mL of the release medium was withdrawn and immediately replaced with an equal volume of fresh buffer to maintain sink conditions. The concentration of the released DOX in the collected samples was quantified using UV–Vis spectroscopy at 480 nm, based on a previously established calibration curve under identical measurement conditions. The cumulative release percentage was calculated using Eq. 3. All experiments were conducted in triplicate to ensure reproducibility (Fathi and Mohammadi 2023 ; Javanbakht et al. 2021 ). $$\:DOX\:release\:\left(\%\right)=\frac{Cumulative\:DOXreleased\:\:\left(mg\right)}{Initial\:DOXloaded\:\:\left(mg\right)}\times\:100\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\:\left(3\right)$$ 2.5. Storage stability and Colloidal stability study The storage stability of the Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS/DOX nanocomposite was systematically investigated, considering the physicochemical characteristics of the nanoparticles, the functional properties of the surface coatings, and the molecular sensitivity of DOX. To evaluate storage stability within the nanocarrier system, Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS nanocarriers were synthesized, loaded with DOX, and subsequently stored under controlled environmental conditions (5, 25, 50, and 100°C) for seven days in both dark and sunlight-exposed settings. Following the storage period, the release behavior of DOX was assessed at pH 5 and 41°C (Foroutan et al. 2025c ). The colloidal stability of the Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS/DOX nanocomposite under physiological conditions (pH 7.4) was systematically investigated. The nanocomposite was dispersed in 3 mL of PBS (pH 7.4) and incubated at 37°C for 7 days. Changes in hydrodynamic diameter were determined by dynamic light scattering (DLS) at predetermined time intervals to evaluate the stability of the dispersion under physiological conditions (Silva-Neto et al. 2025 ). 2.6. Cytotoxicity study The cytotoxicity of DOX-loaded nanocarriers, including Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS/DOX, Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS, and free DOX, was evaluated using the MTT assay. A549 cells were seeded in 96-well plates at a density of 8,000–10,000 cells per well in 200 µL of culture medium and incubated overnight at 37°C. Cells were then treated with different concentrations of the samples and incubated for 48 h under dark or CO 2 -controlled conditions. For biocompatibility evaluation, cells were exposed to the corresponding blank nanocarriers. After incubation, the medium was replaced with fresh medium containing 20 µL of MTT solution (5 mg/mL) and incubated for 3–4 h at 37°C to allow formazan formation. Finally, 200 µL of DMSO was added to dissolve the formazan crystals, and the absorbance was measured at 570 nm using a microplate reader. All assays were carried out in triplicate to validate the consistency and reproducibility of the data (Karimi and Namazi 2021 ; Naik et al. 2023 ). 2.7. DAPI staining To further assess the therapeutic efficacy and potential biomedical applicability of the Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS/DOX nanocomposite, its cellular internalization behavior was systematically evaluated in comparison with free DOX using fluorescence microscopy. A549 cells were cultured in 24-well plates and treated with either the DOX-loaded nanocomposite or free DOX at concentrations corresponding to the IC 50 values obtained from the MTT assay. After 48 h incubation at 37°C under standard cell culture conditions, the cells were thoroughly rinsed with phosphate-buffered saline (PBS) to eliminate residual extracellular compounds and subsequently fixed with 4% paraformaldehyde for 15 min at room temperature. Nuclear staining was performed using DAPI under light-protected conditions. Fluorescence images were then acquired to visualize intracellular drug localization and distribution, thereby providing qualitative insight into the cellular uptake efficiency of the nanocomposite system (Javanbakht and Mohammadi 2025 ). 2.8. Statistical analysis Statistical significance was determined using one-way analysis of variance (ANOVA) followed by Tukey’s post-hoc test. All analyses were performed using GraphPad Prism software (version 9.0.0). Data are expressed as the mean ± standard deviation (SD). 3. Results and discussion 3.1. FT-IR analysis FT-IR spectroscopy was employed to investigate the functional groups of the synthesized materials, as depicted in Fig. 1 . In the Fe 3 O 4 spectrum, distinct absorption bands appear near 555 cm⁻¹ and 3392 cm⁻¹, which can be assigned to the Fe–O stretching mode of the spinel structure and the O–H stretching vibrations of surface hydroxyl groups, respectively (Foroutan et al. 2025b ; Bochong Wang et al. 2022a ). In Fig. 1 b, a strong band appears in the range of 1080–1100 cm − 1 , which is attributed to the asymmetric stretching vibrations of Si–O–Si bonds (Barutiak et al. 2025 ). This characteristic band confirms the formation of the silica network and indicates the successful coating of the Fe 3 O 4 NPs with the SiO 2 layer. In Fig. 1 c, the appearance of a peak around 1620 cm − 1 , corresponding to C–O stretching vibrations, along with the retention of characteristic peaks of Fe 3 O 4 @SiO 2 NPs, provides clear evidence for the successful coating of Fe 3 O 4 @SiO 2 with Dex (Mokhtari et al. 2024 ). Figure 1 d and e display a weak absorption band around 1718 cm − 1 , corresponding to C = O and C = N stretching vibrations, which confirms the presence of aldehyde and imine functional groups in Fe 3 O 4 @SiO 2 @Dex and Fe 3 O 4 @SiO 2 @Dex-DA. As shown in Fig. 1 f, the absorption bands located at around 3438 cm − 1 and 1612 cm − 1 are attributed to the stretching and bending vibrations of –NH 3 + groups, respectively. Furthermore, the distinct peak observed at 1124 cm − 1 , corresponding to the asymmetric stretching vibration of Si–O–Si bonds, confirms the well-defined formation of the Si–O–Si network, indicating the successful synthesis of OA–POSS (Gohari et al. 2023 ). 3.2. VSM and XRD analyses The XRD profiles of Fe 3 O 4 , Fe 3 O 4 @SiO 2 @Dex, and Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS NPs are illustrated in Fig. 2 A. As shown, the characteristic diffraction peaks appearing at 2θ values of 30.6, 35.4, 43.5, 53.8, 57.6, and 62.7 degrees are associated with the (220), (311), (420), (422), (511), and (440) crystallographic planes of Fe 3 O 4 . These diffraction peaks exhibit excellent agreement with the standard Fe 3 O 4 reference pattern, thereby substantiating the preservation of the spinel crystal structure in the synthesized NPs. Following the surface modification of Fe 3 O 4 NPs with SiO 2 and Dextran, a broad diffraction band becomes evident at 2θ ≈ 20–25°, which is characteristic of the presence of an amorphous silica coating surrounding the magnetic core (Kutluay et al. 2021 ; Patil et al. 2023 ). In the final bio-nanocomposite, Fe 3 O 4 @SiO 2 @Dex–DA@OA-POSS (Fig. 2 c), this amorphous signal becomes substantially more pronounced, appearing as a stronger and broader amorphous halo region within the 15–30° range. The intensified amorphous background arises from the introduction of OA-POSS and DA-modified Dextran, both contributing non-crystalline components to the overall structure. The progressive enhancement of the amorphous region, together with the persistent and well-defined diffraction peaks of Fe 3 O 4 , confirms that each functional layer has been successfully incorporated while preserving the crystalline spinel structure of the magnetite core. This XRD behavior provides clear evidence of effective sequential surface modification without any detrimental impact on the core crystallinity (Jia et al. 2021 ). Based on the obtained magnetization curves (Fig. 2 B), the saturation magnetization values of Fe 3 O 4 @SiO₂ and Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS were determined to be 54 and 19 emu g⁻¹, respectively. The marked reduction in magnetic intensity observed for Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS is attributed to the presence of the non-magnetic Dex and OA-POSS layers coating the Fe 3 O 4 @SiO 2 NPs, which diminishes the overall contribution of the magnetic core. Following their potential accumulation at the diseased site, exposure to an alternating magnetic field could, in principle, enable localized heat generation through magnetic hyperthermia. This thermal stimulus may potentially facilitate the release of therapeutics from thermoresponsive matrices or induce structural perturbations of the NC, thereby promoting on-demand drug liberation at the target location (Lucaciu 2024 ). In addition to hyperthermia, magnetically induced drug release might also arise from the mechanical oscillation of MNPs under a pulsed magnetic field. While these mechanisms highlight the system’s theoretical potential, experimental validation under magnetic field exposure remains to be conducted. Such oscillatory motion can compromise the integrity of lipid membranes, ultimately facilitating intracellular release of the encapsulated agents. The characteristic S-shaped VSM profiles further confirm the superparamagnetic nature of the Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS NPs and underscore their capacity for spatially controlled drug release in response to an external magnetic field (Dwivedi and Dwivedi 2025 ; Mohammadzadeh et al. 2024a ). 3.3. DLS and SEM analyses In the SEM images, the sample exhibits a distinctly rough, heterogeneous, and highly aggregated morphology, which is typical of hybrid organic–inorganic nanocomposites. The presence of Fe 3 O 4 is confirmed by the ultrafine granular domains and clusters of spherical nanoparticles distributed throughout the structure. Such agglomerated assemblies arise from strong interparticle magnetic interactions that promote the formation of dense magnetic clusters (Fig. 3 a). The absence of individually dispersed NPs, along with the complete encapsulation of these magnetic clusters, indicates the successful formation of a continuous shell composed of SiO 2 and polymeric layers. The soft, amorphous, and smooth-edged surface regions correspond to the Dex-DA polymer coating, which typically produces a non-crystalline, cloud-like morphology after deposition on the silica surface. Moreover, the nanoscale protrusions and nodular surface roughness, observed as fine granular elevations, are characteristic of materials containing POSS units (Fig. 3 b). The cage-like silsesquioxane framework of OA-POSS is known to impart this granular nano-roughness to hybrid nanocomposites (Fig. 3 c). The concurrent presence of these morphological signatures, namely the Fe 3 O 4 magnetic clusters, the polymer rich Dex-DA surface, and the nanoscale granular features associated with OA-POSS, strongly supports the successful integration of all components within the Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS NC. Collectively, these structural observations provide compelling evidence for the proper assembly of the intended multilayer nanoplatform, confirming its suitability for targeted drug delivery applications (Chang et al. 2024 ; Jia et al. 2021 ). The mean hydrodynamic diameters of Fe 3 O 4 @SiO 2 @Dex and Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS nanocomposites were quantitatively analyzed by DLS, yielding values of approximately 183 nm and 197 nm, respectively, as illustrated in Figs. 3 e and 3 d. NPs within the 100–200 nm size range are widely recognized as optimal dimensions for DDSs due to their ability to evade rapid renal clearance and minimize recognition and uptake by the reticuloendothelial system (RES). This size range also facilitates enhanced passive targeting via the enhanced permeability and retention (EPR) effect, enabling accumulation in tumor tissues, particularly when combined with external magnetic guidance. Furthermore, the Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS nanocomposites exhibited a positive zeta potential averaging + 19.6 mV, indicative of a positively charged nanoparticle surface. Such a surface charge contributes substantially to colloidal stability by preventing aggregation and promotes increased cellular uptake through electrostatic attraction to the negatively charged phospholipid membranes of cancer cells, thereby potentially improving intracellular delivery efficiency (Forest and Pourchez 2017 ). 3.4. In vitro DOX loading and release studies To evaluate the efficacy of the synthesized nanocarriers in drug delivery, DOX was selected as a representative therapeutic agent to measure both drug encapsulation efficiency (DEE) and release kinetics. At a DOX to carrier weight ratio of 1:10, the Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS nanocomposite exhibited a DEE of 95 ± 0.5%, while Fe 3 O 4 @SiO 2 @Dex achieved 80 ± 0.5% (Fig. 4 C). It should be clarified that this value refers to DEE, which represents the amount of DOX encapsulated within the nanocarriers relative to the total amount of DOX used in the formulation. The significantly enhanced loading capacity observed in the OA-POSS functionalized nanocomposite is attributed to the presence of additional functional groups introduced by OA-POSS, which promote stronger intermolecular interactions with DOX molecules. These include hydrogen bonding, possible π–π stacking interactions involving the aromatic rings of DOX, interactions with carbonyl groups within the polymeric matrix, as well as physical entrapment of the drug within the dense hybrid shell structure, collectively contributing to improved drug retention within the nanocarrier matrix. Release experiments conducted at pH 5 revealed that approximately 81 ± 0.5% of DOX was released from Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS, whereas about 71 ± 0.5% was released from Fe 3 O 4 @SiO 2 @Dex over a period of 144 h. As illustrated in Fig. 4 A, the slower release profile observed for the OA-POSS modified NC is attributed to the imine bonds formed between OA-POSS and Dex-DA, which reinforce and stabilize the nanoparticle coating. These covalent bonds effectively suppress the initial burst release of DOX by reinforcing the structural integrity of the coating. Moreover, the three-dimensional structure of OA-POSS, along with its higher density of reactive groups, creates steric hindrance and additional physical barriers, which help regulate drug diffusion and promote a more sustained release. In contrast, Fe 3 O 4 @SiO 2 @Dex lacks these reinforcing covalent bonds and the associated stabilized multilayer shell, resulting in a more rapid drug release. Notably, the Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS/DOX formulation exhibited the lowest DOX release at physiological pH (7.4) (Fig. 4 B), a critical characteristic for systemic administration that potentially minimizes off-target toxicity and reduces adverse side effects associated with DOX treatment (Tao et al. 2018 ). Furthermore, the DOX release profiles obtained for the Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS NC were fitted to four conventional kinetic models (Table 1 ). Analysis of the corresponding R² coefficients demonstrated clear pH-dependent variations in release behavior. Such variations likely arise from pH-induced alterations in the physicochemical characteristics of the carrier matrix, which modify the predominant mechanism governing drug diffusion and release. The deviation of Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS at pH 5 from the Weibull model, and its better fit to the Higuchi model, is likely due to acid induced changes in the OA-POSS reinforced coating, including partial imine hydrolysis and increased porosity. These alterations shift the release mechanism toward a predominantly diffusion-controlled process, which aligns more closely with Higuchi kinetics under acidic conditions. Overall, the findings demonstrate that Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS/DOX nanocomposites provide a markedly prolonged release of DOX under acidic tumor-like conditions, underscoring their promise as a potent platform for targeted anticancer drug delivery. 3.5. DOX storage stability The results presented in Fig. 5 demonstrate that exposure to elevated temperatures and light markedly decreases the storage stability of the nanocarriers, evidenced by reduced DOX release. This reduction is attributed to thermally and photochemically induced degradation of the drug, which compromises its retention within the nanocarrier matrix. Consistent with the Arrhenius equation (Eq. 4), the rate of degradation reactions escalates with increasing temperature, thereby accelerating DOX decomposition. Consequently, optimal storage conditions for maintaining nanocarrier integrity and drug stability are achieved in darkness at temperatures between 5 and 50°C. Furthermore, the colloidal stability of the final nanocomposite at pH 7.4 was evaluated over 7 days through hydrodynamic size measurements, and the results are provided in the Supporting Information (Fig. S1). $$\:k=A{e}^{\frac{{-E}_{a}}{RT}}$$ 4 3.6. MTT assay The cytotoxicity and biocompatibility of the synthesized NCs were examined in A549 cells utilizing the MTT assay. As shown in Fig. 6, the unloaded Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS NCs exhibited excellent cytocompatibility, maintaining over 85% cell viability at a concentration of 0.5 µg/mL. This high level of cell survival suggests that the NC itself is inherently safe and well-tolerated by the cells, making it a suitable candidate for drug delivery applications. In contrast, when A549 cells were treated with DOX loaded Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS NCs, a significant reduction in cell viability was observed. Notably, the DOX loaded nanocomposite induced stronger cytotoxic effects than free DOX at the same drug concentration. This enhanced anticancer activity can be explained by the nanoscale size and surface characteristics of the carrier, which facilitate more efficient cellular uptake and increase intracellular accumulation of DOX. Consequently, the drug exerts its therapeutic effect more intensely than when administered in its free molecular form. Overall, these findings indicate that Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS/DOX represents a promising and effective nanoplatform for targeted anticancer drug delivery systems, combining biocompatibility with improved therapeutic performance. 3.7. Cellular apoptosis studies To further confirm the results obtained from the MTT assay, fluorescence imaging was conducted on A549 cells after different treatments. DAPI staining was used as a nuclear fluorescent dye to observe apoptosis-related changes, since it binds strongly to DNA and allows clear visualization of nuclear morphology. Through this approach, features such as chromatin condensation and nuclear fragmentation could be detected. In this study, DAPI staining combined with fluorescence microscopy was applied to evaluate structural changes in the nuclei of treated A549 cells and to qualitatively assess the induction of apoptosis. To evaluate cytocompatibility and anticancer efficacy, A549 cells were treated with Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS, Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS/DOX, free DOX, and an untreated control group. Fluorescence images obtained following DAPI staining revealed a higher cell density in the Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS treated group, confirming the favorable biocompatibility of the nanocomposites (Fig. 7b). Conversely, cells treated with Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS/DOX exhibited a markedly greater reduction in viability compared with those receiving free DOX (Fig. 7c, d). The improved cytotoxic performance can be attributed to the nanoscale dimensions of the synthesized nanoparticles, which enhance tumor tissue penetration and cellular internalization. Collectively, the DAPI staining results demonstrate that Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS/DOX efficiently induces apoptotic cell death, underscoring its potential as an effective drug delivery platform for cancer therapy. 4. Conclusion In this work, a pH-responsive core–shell magnetic nanocomposite incorporating OA-POSS, Dex, and Fe 3 O 4 NPs via a Schiff-base imine reaction was developed to improve targeted cancer treatment. The imine bond is responsible for the pH-responsive behavior, remaining stable at physiological pH and cleaving under acidic conditions to enable controlled DOX release. Introducing OA-POSS onto the NP surface significantly enhanced the DEE to approximately 95%, mainly due to the formation of hydrogen bonds and electrostatic attractions between DOX and the POSS groups. In vitro release studies confirmed a pronounced pH-responsive profile, with negligible DOX release (11 ± 0.5%) at physiological pH 7.4, while acidic conditions at pH 5 induced a sustained release of 81 ± 0.5% over 6 days. As a result, the initial burst release of the drug is minimized, which in turn reduces systemic toxicity and lowers the risk of adverse side effects. Based on cytotoxicity assessments against A549 cells, the optimal dose of this drug-loaded system is estimated to be approximately 1 µg/mL, corresponding to the determined IC 50 value. Additionally, in vitro cytotoxicity assessments, along with DAPI staining, revealed that the Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS/DOX nanocomposite exhibited markedly enhanced anticancer activity against A549 cells compared with free doxorubicin. This improved cytotoxicity is likely related to the small particle size of the nanocomposite, which enhances penetration into tumor tissues and increases cellular uptake of the drug. Altogether, these results show that the proposed nanosystem not only improves the therapeutic potential of DOX but also represents a promising platform for more accurate and effective cancer-targeted drug delivery. Declarations Funding sources This work received no external funding. authorship contribution Ramezan Ali Taheri : Formal analysis, writing—review & editing. Ali Mohammadzadeh: Data curation, Software, Conceptualization, Visualization, Investigation, Writing—original draft, Project administration, Validation, Methodology. Reza Mohammadi: Data curation. Ramin Karimian : Formal analysis, writing—review & editing. Mohammad Reza Khodabakhshi: Resources, supervision, writing—review & editing, validation. Declaration of Competing Interest The authors declare no conflicts of interest. Data availability Data will be made available on request Acknowledgments The authors would like to express their sincere gratitude to all collaborators who contributed to this research. Their valuable assistance, insightful discussions, and technical support are greatly appreciated. References Arsalani N, Kazeminava F, Akbari A, Hamishehkar H, Jabbari E, Kafil HS (2019) Synthesis of polyhedral oligomeric silsesquioxane nano-crosslinked poly (ethylene glycol)‐based hybrid hydrogels for drug delivery and antibacterial activity. Polym Int 68(4):667–674 Barutiak M, Zeleňáková A, Hrubovčák P, Nagy L, Szűcsová J, Fabriciová Ž., Beňová E, Király N, Zeleňák V, Antošová A (2025) Enhanced efficiency of fe3o4@ sio2 with specific ligand layer in magnetic separation technique. Surfaces and Interfaces:107252 Beach MA, Nayanathara U, Gao Y, Zhang C, Xiong Y, Wang Y, Such GK (2024) Polymeric nanoparticles for drug delivery. Chem Rev 124(9):5505–5616 Bijudas K, Megha S, Greeshma G, Reshma R, Jiju K (2025) Hyaluronic acid-coated zeolitic imidazolate framework (zif-67) for the targeted and ph-responsive drug delivery system. J Inorg Organomet Polym Mater :1–11 Chang YK, Hao SJ, Wu FG (2024) Recent biomedical applications of functional materials based on polyhedral oligomeric silsesquioxane (poss). Small 20(48):2401762 Dwivedi R, Dwivedi RK (2025) A comprehensive review on conducting polymers for multifaceted applications. J Inorg Organomet Polym Mater :1–39 Fathi R, Mohammadi R (2023) Preparation of ph-responsive magnetic nanocomposite hydrogels based on k-carrageenan/chitosan/silver nanoparticles: Antibacterial carrier for potential targeted anticancer drug delivery. Int J Biol Macromol 246:125546 Forest V, Pourchez J (2017) Preferential binding of positive nanoparticles on cell membranes is due to electrostatic interactions: A too simplistic explanation that does not take into account the nanoparticle protein corona. Mater Sci Engineering: C 70:889–896 Foroutan R, Mohammadzadeh A, Mohammadi R, Javanbakht S (2025a) Carboxymethyl cellulose/hydroxyapatite/fe3o4 bio-nanocomposite hydrogel beads: An efficient oral ph-responsive carrier for doxorubicin delivery. Chem Pap :1–10 Foroutan R, Mohammadzadeh A, Mohammadi R, Javanbakht S (2025b) Carboxymethyl cellulose/hydroxyapatite/fe3o4 bio-nanocomposite hydrogel beads: An efficient oral ph-responsive carrier for doxorubicin delivery. Chem Pap 79(4):2461–2470 Foroutan R, Mohammadzadeh A, Javanbakht S, Mohammadi R, Ghorbani M (2025c) Alginate/magnetic hydroxyapatite bio-nanocomposite hydrogel bead as a ph-responsive oral drug carrier for potential colon cancer therapy. Results Chem 15:102177 Ghasemi S, Karimzadeh M, Kafshboran HR (2025) Magnetically recoverable gold catalyst supported on pvim-grafted fe₃o₄@ cqd composite for efficient nitroarene reduction in water. J Organomet Chem :123941 Gohari G, Panahirad S, Mohammadi A, Kulak M, Dadpour MR, Lighvan ZM, Eftekhari-Sis SS, Szafert B, Fotopoulos S V (2023) Characterization of octa-aminopropyl polyhedral oligomeric silsesquioxanes (oa-poss) nanoparticles and their effect on sweet basil (ocimum basilicum l.) response to salinity stress. Plant Physiol Biochem 196:89–102 Guo H, Lei B, Yu J, Chen Y, Qian J (2021) Immobilization of lipase by dialdehyde cellulose crosslinked magnetic nanoparticles. Int J Biol Macromol 185:287–296 Hosseinzadeh H, Vahdatkhah A, Javanbakht S, Mohammadi R (2025) Synthesis of ph-responsive hollow molecularly imprinted polymers for enhanced doxorubicin delivery in cancer therapy. J Pharm Sci :103993 Javanbakht S, Nabi M, Shaabani A (2021) Graphene quantum dots-crosslinked gelatin via the efficient ugi four-component reaction: Safe photoluminescent implantable carriers for the ph-responsive delivery of doxorubicin. Materialia 20:101233 Javanbakht S, Mohammadi R (2025) Chondroitin sulfate-decorated cupper-benzene dicarboxylate framework as an efficient passive and active targeting nanomedicine for anticancer methotrexate delivery. International Journal of Pharmaceutics: X:100403 Jia P, Cheng W, Lu J, Yin Z, Xu Z, Cheng L, Qiu Y, Qian L, Hu Y, Hu W (2021) Applications of go/oa-poss layer‐by‐layer self‐assembly nanocoating on flame retardancy and smoke suppression of flexible polyurethane foam. Polym Adv Technol 32(11):4516–4530 Karimi S, Namazi H (2021) Fe3o4@ peg-coated dendrimer modified graphene oxide nanocomposite as a ph-sensitive drug carrier for targeted delivery of doxorubicin. J Alloys Compd 879:160426 Kutluay S, Horoz S, Şahin Ö, Ekinci A, Ece MŞ (2021) Highly improved solar cell efficiency of mn-doped amine groups‐functionalized magnetic fe3o4@ sio2 nanomaterial. Int J Energy Res 45(14):20176–20185 Liang Y, Xu J, Ahmed N, Shi J, Wen M, Yan N (2024) Construction of biomass-based flame-retardant, antimicrobial and hydrophobic wood coatings with poss organic-inorganic nanoparticles. Eur Polymer J 219:113370 Linders AN, Dias IB, López Fernández T, Tocchetti CG, Bomer N, Van der Meer P (2024) A review of the pathophysiological mechanisms of doxorubicin-induced cardiotoxicity and aging. npj Aging 10(1):9 Liu B, Zhou H, Tan L, Siu KTH, Guan X-Y (2024a) Exploring treatment options in cancer: Tumor treatment strategies. Signal Transduct Target therapy 9(1):175 Liu Y, Liang Y, Yuhong J, Xin P, Han JL, Du Y, Yu X, Zhu R, Zhang M, Chen W (2024b) Advances in nanotechnology for enhancing the solubility and bioavailability of poorly soluble drugs. Drug design, development and therapy:1469–1495 Loman-Cortes P, Binte Huq T, Vivero-Escoto JL (2021) Use of polyhedral oligomeric silsesquioxane (poss) in drug delivery, photodynamic therapy and bioimaging. Molecules 26(21):6453 Long H, Ryu S, Zheng X-L, Zhang L-S, Li L-Y, Zhang Z-S (2023) Peptide l1h9 derived from the interaction of structural human rhomboid family 1 and 80-kda subunit of ku antigen sensitizes breast cancer to chemoradiotherapy. Adv Compos Hybrid Mater 6(6):208 Lucaciu CM (2024) Magnetic nanomaterials for hyperthermia-based therapy, imaging, and drug delivery. MDPI, p 263 Mohammadzadeh A, Javanbakht S, Mohammadi R (2024a) Magnetic alginate core-shell nanoparticles based on schiff-base imine bonding for ph-responsive doxorubicin delivery system. Colloids Surf A 697:134473 Mohammadzadeh A, Javanbakht S, Mohammadi R, Kazeminava F (2024b) Ferrocene-functionalized magnetic core-shell nanoparticles based on hydrosilylation reaction for ph-responsive doxorubicin delivery system. Colloids Surf A 703:135201 Mohammadzadeh A, Javanbakht S, Mohammadi R (2025) Encapsulation of nh2-mil-101 (fe) with dialdehyde starch through schiff-base imine: A development of a ph-responsive core-shell fluorescent nanocarrier for doxorubicin delivery. Carbohydr Polym Technol Appl 10:100794 Mokhtari F, Poladian M, Shamloo A (2024) A method for macromolecule transport to the spinal cord nervous system trauma with a combination of ultrasound and magnetic fields. Int J Nano Dimension, 15(1 (January 2024)). Naik N, Adeyanju O, Samrot AV, Bhat P, Salmataj S (2023) Drug delivery through microneedles for improved permeability and efficacy: Fabrication, methodology and applications. Eng Sci 26:1065 Ngwu-Hyacinth O, Alford A, Rowe CS, Willoughby R, Mirbozorgi SA, Rothenberg SA, Jones J, Sajan A, Krishnasamy VP, Bolding M (2025) Ultrasmall superparamagnetic iron oxide nanoparticles as positive contrast agents in low‐field magnetic resonance imaging. Iradiology 3(5):372–387 Nordin AH, Ahmad Z, Husna SMN, Ilyas RA, Azemi AK, Ismail N, Nordin ML, Ngadi N, Siti NH, Nabgan W (2023) The state of the art of natural polymer functionalized fe3o4 magnetic nanoparticle composites for drug delivery applications: A review. Gels 9(2):121 Patil PJ, Dong X, Usman M, Bhambore NR, Shah H, Zhang C, Li X (2023) Recent trends in metal-organic frameworks mediated lipase immobilization: A state‐of‐the‐art review. Food Saf Health 1(2):139–169 Petrovici AR, Pinteala M, Simionescu N (2023) Dextran formulations as effective delivery systems of therapeutic agents. Molecules 28(3):1086 Prasad RD, Prasad NR, Prasad RB, Prasad RY, Prasad SR, Gour M, Vaidya AK, Patil M, Patil S, Karmuse S (2023) A critical review on bio-mimetic synthesis of transition metal nanoparticles: Their biomedical applications in veterinary medicine. ES Food Agrofor 15:1027 Rahimkhoei V, Alzaidy AH, Abed MJ, Rashki S, Salavati-Niasari M (2024) Advances in inorganic nanoparticles-based drug delivery in targeted breast cancer theranostics. Adv Colloid Interface Sci 329:103204 Ramasundaram S, Saravanakumar G, Sobha S, Oh TH (2022) Dextran sulfate nanocarriers: Design, strategies and biomedical applications. Int J Mol Sci 24(1):355 Sanson C, Schatz C, Le Meins J-F, Soum A, Thévenot J, Garanger E, Lecommandoux S (2010) A simple method to achieve high doxorubicin loading in biodegradable polymersomes. J Controlled Release 147(3):428–435 Shaikh MAJ, Alharbi KS, Almalki WH, Imam SS, Albratty M, Meraya AM, Alzarea SI, Kazmi I, Al-Abbasi FA, Afzal O (2022) Sodium alginate based drug delivery in management of breast cancer. Carbohydr Polym 292:119689 Shang J, Zhang S, Qiu X, Zhang J, Lin K, Xia D, Zhang L, Yang Y (2025) Recent advances in modification and application of polyhedral oligomeric silsesquioxane/polyurethane composites: A comprehensive review. Macromol Rapid Commun 46(19):e00337 Sharifianjazi F, Irani M, Esmaeilkhanian A, Bazli L, Asl MS, Jang HW, Kim SY, Ramakrishna S, Shokouhimehr M, Varma RS (2021) Polymer incorporated magnetic nanoparticles: Applications for magnetoresponsive targeted drug delivery. Mater Sci Engineering: B 272:115358 Shokri M, Mojtabavi S, Jafari-Nodoushan H, Vojdanitalab K, Golshani S, Jahandar H, Faramarzi MA (2022) Laccase-loaded magnetic dialdehyde inulin nanoparticles as an efficient heterogeneous natural polymer-based biocatalyst for removal and detoxification of ofloxacin. Biodegradation 33(5):489–508 Silva-Neto AF, de Carvalho Amaral AR, de Alencar Danda LJ, Chaves LL, Alves LDS, Soares M. F. d. L. R., Soares-Sobrinho JL (2025) Decoding excipients in lipid-based self-emulsifying drug delivery systems: Insights into physicochemical properties and therapeutic outcomes. International Journal of Pharmaceutics:126018 Tao Y, Liu S, Zhang Y, Chi Z, Xu J (2018) A ph-responsive polymer based on dynamic imine bonds as a drug delivery material with pseudo target release behavior. Polym Chem 9(7):878–884 Tenchov R, Hughes KJ, Ganesan M, Iyer KA, Ralhan K, Lotti Diaz LM, Bird RE, Ivanov JM, Zhou QA (2025) Transforming medicine: Cutting-edge applications of nanoscale materials in drug delivery. ACS Nano 19(4):4011–4038 Vagena I-A, Malapani C, Gatou M-A, Lagopati N, Pavlatou EA (2025) Enhancement of epr effect for passive tumor targeting: Current status and future perspectives. Appl Sci 15(6):3189 van der Merwe L, Kaschula CH, Chellan P (2025) Organometallic conjugates of artesunate: Synthesis and evaluation of anticancer potential. J Organomet Chem :123804 Venkataraman S, Hedrick JL, Ong ZY, Yang C, Ee PLR, Hammond PT, Yang YY (2011) The effects of polymeric nanostructure shape on drug delivery. Adv Drug Deliv Rev 63(14–15):1228–1246 Wang B, Ji Y, Mu C, Huo Y, Xiang J, Nie A, Xue T, Zhai K, Liu Z, Wen F (2022a) Well-controlled core-shell structures based on fe3o4 nanospheres coated by polyaniline for highly efficient microwave absorption. Appl Surf Sci 591:153176 Wang Q, Chen J, Ling J, Zhao H, Ouyang X-k, Wang N (2024) Metal-polyphenol network coated photothermal nanocarriers for ph-activated drug delivery. Mater Today Chem 35:101892 Wang Z, Li R, Zhang J (2022b) On-demand drug delivery of triptolide and celastrol by poly (lactic-co-glycolic acid) nanoparticle/triglycerol monostearate-18 hydrogel composite for rheumatoid arthritis treatment. Adv Compos Hybrid Mater 5(4):2921–2935 Yang W, Su L, Wang L, Wu J, Chen S (2022) Alpha-glucanotransferase from the glycoside hydrolase family synthesizes α (1–6)-linked products from starch: Features and synthesis pathways of the products. Trends Food Sci Technol 128:160–172 Yu H, Hao P, Si P, Wang B, Shen Q, Zhu H, Lin W, Hu Q (2024) A mn-based metal-organic framework mn-cpp for combined chemodynamic therapy and chemotherapy. J Organomet Chem 1019:123305 Yu Y, Xu Q, He S, Xiong H, Zhang Q, Xu W, Ricotta V, Bai L, Zhang Q, Yu Z (2019) Recent advances in delivery of photosensitive metal-based drugs. Coord Chem Rev 387:154–179 Zhou H, Li C, Zhang Y, Tu W, Li Q, Peng Y, Zhang Z, Zheng Z (2025) Nano-sio2/pvc composite material: A review on modification, preparation, properties, and applications. J Appl Polym Sci 142(42):e57605 Zuo X, Pan L, Zhang W, Zhu J, Qin Y, Xu X, Wang Q (2024) The discovery, molecular cloning, and characterization of dextransucrase lm dexa and its active truncated mutant from leuconostoc mesenteroides nn710. Molecules 29(13):3242 Scheme 1 Scheme 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Scheme1.png Scheme 1. The representation of the Fe 3 O 4 @SiO 2 @Dex-DA@OA-POSS/DOX preparation. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 11 May, 2026 Reviews received at journal 09 May, 2026 Reviewers agreed at journal 04 May, 2026 Reviewers agreed at journal 03 May, 2026 Reviews received at journal 01 May, 2026 Reviewers agreed at journal 21 Apr, 2026 Reviewers invited by journal 20 Apr, 2026 Editor assigned by journal 20 Apr, 2026 Submission checks completed at journal 20 Apr, 2026 First submitted to journal 14 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9419286","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":628226063,"identity":"27894dd1-0bab-4fd3-9e24-d27f4bfca549","order_by":0,"name":"Ramezan Ali Taheri","email":"","orcid":"","institution":"Baqiyatallah University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ramezan","middleName":"Ali","lastName":"Taheri","suffix":""},{"id":628226064,"identity":"0b7bd4e1-24db-4e1a-91fd-aed6488b1968","order_by":1,"name":"Ali Mohammadzadeh","email":"","orcid":"","institution":"University of Tabriz","correspondingAuthor":false,"prefix":"","firstName":"Ali","middleName":"","lastName":"Mohammadzadeh","suffix":""},{"id":628226065,"identity":"a72e2147-6d03-4997-a3e7-a9955c4e9610","order_by":2,"name":"Reza Mohammadi","email":"","orcid":"","institution":"University of Tabriz","correspondingAuthor":false,"prefix":"","firstName":"Reza","middleName":"","lastName":"Mohammadi","suffix":""},{"id":628226066,"identity":"01824612-e489-4993-9b3c-bb79b1ffe865","order_by":3,"name":"Mohammad Reza Khodabakhshi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAklEQVRIiWNgGAWjYBACgxsMDBKMDQwGBgw8DAc+NsDFcWsxnIGk5eBMYrQYSyBpYeZtwK0SDsykmw/e+LnDztic/+zBw7Y7ttkbHGB++IGh4B5OLTYyx5Ite88km1nOyEs4nHvmduKGA2xAqw2KcWuRyDGT4G1jtjG4wWNwOLftdoLBAQYzoF8ScDsMqEXyb1u9jcH5MwaHLdtuAx3G/g2vFmOgFmnetsNmBgdyDA4ztt1m3HCAB78thjPSkq1lzxw3NriRY3CwF+iXmYd5iiUS8GgxuJF88ObbHdWGG86fMf7wc8dte77j7Rs/fPiDWwsWwAzEJGkYBaNgFIyCUYABAH8YWaYVWb/FAAAAAElFTkSuQmCC","orcid":"","institution":"Baqiyatallah University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Mohammad","middleName":"Reza","lastName":"Khodabakhshi","suffix":""},{"id":628226067,"identity":"9ebaa175-d4ca-4cbd-bf5d-d3df029fe9f0","order_by":4,"name":"Ramin Karimian","email":"","orcid":"","institution":"Baqiyatallah University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ramin","middleName":"","lastName":"Karimian","suffix":""}],"badges":[],"createdAt":"2026-04-14 20:08:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9419286/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9419286/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108149537,"identity":"6e7df8c2-5aa6-4c95-aa33-6d61f3fdfe73","added_by":"auto","created_at":"2026-04-29 23:34:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":222025,"visible":true,"origin":"","legend":"\u003cp\u003eFT-IR spectra of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e (a), Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e (b), Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex (c), Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA (d), Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS (e), OA-POSS (f).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-9419286/v1/b220accba8b49ec945c5580d.png"},{"id":108182420,"identity":"c2083e7d-2355-4366-8311-e29817322797","added_by":"auto","created_at":"2026-04-30 08:59:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":181881,"visible":true,"origin":"","legend":"\u003cp\u003e(A) XRD spectra of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e (a), Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex (b), Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS (c). (B) The VSM curves of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e (a), Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS (b).\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-9419286/v1/1535307e7980547e476e2cba.png"},{"id":108149540,"identity":"e2932613-a429-40e5-b11a-7edf68f40986","added_by":"auto","created_at":"2026-04-29 23:34:25","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":328989,"visible":true,"origin":"","legend":"\u003cp\u003eSEM images of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e (a), OA-POSS (b), and Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS (c). Particle size distributions of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex (e) and Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS (d).\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-9419286/v1/974551689be9e6856a5de08d.png"},{"id":108182982,"identity":"a856854c-91df-41db-8e78-31bc91cab035","added_by":"auto","created_at":"2026-04-30 08:59:43","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":202266,"visible":true,"origin":"","legend":"\u003cp\u003eDOX loading (C) and cumulative release profiles of DOX from Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX and Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex/DOX at pH 7.4, 5.0, and 37 °C.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-9419286/v1/f53380409d7b85a1cf683efb.png"},{"id":108149541,"identity":"901505ae-4f40-4f5a-9f74-a81e28e3b952","added_by":"auto","created_at":"2026-04-29 23:34:25","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":119541,"visible":true,"origin":"","legend":"\u003cp\u003eDOX storage stability for Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX NC during 7 days.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-9419286/v1/23bf008888bf83dd85629a59.png"},{"id":108149543,"identity":"773d6b0b-dbed-4f35-9afa-544c70f30964","added_by":"auto","created_at":"2026-04-29 23:34:25","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":204028,"visible":true,"origin":"","legend":"\u003cp\u003eMTT result of A549 cells after 48 h incubation with various concentrations of\u003cstrong\u003e \u003c/strong\u003eFe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX, Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS, and free DOX (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05).\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-9419286/v1/c14e1a9fb30c99ca9068cb3b.png"},{"id":108149544,"identity":"2438fc0b-1146-4c59-8ff1-cec7073b831d","added_by":"auto","created_at":"2026-04-29 23:34:25","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":143103,"visible":true,"origin":"","legend":"\u003cp\u003eDAPI staining of A549 cells after 48 h of incubation. (a) Control (untreated); treated with (b) Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS; (c) Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX (c′: DOX fluorescence); and (d) free DOX (d′: DOX fluorescence) (Magnification factor: 40 x).\u003c/p\u003e","description":"","filename":"floatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-9419286/v1/8c6f3c87c1a446ce9b41d2de.png"},{"id":108183929,"identity":"a031b576-f3ac-4d73-9a5e-7259e90322bd","added_by":"auto","created_at":"2026-04-30 09:03:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1943164,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9419286/v1/b13bafae-0614-48fe-b63e-9d737d0b9f78.pdf"},{"id":108149538,"identity":"c8867368-5b61-4fc8-b2ca-d6d5eb1e54aa","added_by":"auto","created_at":"2026-04-29 23:34:25","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":517158,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 1. \u003c/strong\u003eThe representation of the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX preparation.\u003c/p\u003e","description":"","filename":"Scheme1.png","url":"https://assets-eu.researchsquare.com/files/rs-9419286/v1/22e8e4dd367aa7fe23e40016.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Octa-aminopropyl polyhedral oligomeric silsesquioxane-functionalized magnetic dextran nanoparticles via dynamic Schiff-base imine bonds for sustained doxorubicin release","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eDoxorubicin (DOX) is an effective anticancer agent that induces cell death by interfering with DNA function and inhibiting cellular proliferation (Mohammadzadeh et al. \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Hongliu Yu et al. \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). However, its therapeutic application is limited by poor selectivity, as it also damages healthy cells, leading to severe side effects such as cardiotoxicity (Linders et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Qiong Wang et al. \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). This challenge is particularly evident in diseases like lung cancer, one of the most common and deadly cancer types, where DOX can effectively suppress tumor cell growth, but its systemic toxicity restricts optimal dosing. To overcome these drawbacks, advanced targeted drug delivery systems (DDSs) have been developed (van der Merwe et al. \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). In these systems, the drug is encapsulated within nanoscale carriers designed to deliver it directly and in a controlled manner to tumor tissues (Tenchov et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). This strategy enhances drug accumulation at the tumor site while minimizing harm to normal tissues and reducing systemic toxicity (Hosseinzadeh et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Beilei Liu et al. \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2024a\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNanoparticles (NPs), a subset of nanoscale drug carriers, are important in targeted drug delivery due to their ability to cross biological barriers and selectively accumulate in tumors \u003cem\u003evia\u003c/em\u003e the enhanced permeability and retention )EPR( effect (Long et al. \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Vagena et al. \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e magnetite NPs (MNPs) are particularly attractive because of their superparamagnetic behavior, biocompatibility, and low toxicity (Foroutan et al. \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2025a\u003c/span\u003e). They can be guided by an external magnetic field and serve both as drug carriers and magnetic resonance imaging (MRI) contrast agents for theranostic applications (Ngwu-Hyacinth et al. \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). Bare MNPs exhibit pronounced chemical reactivity and are prone to oxidation, which may compromise their magnetic properties (Ghasemi et al. \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). Consequently, it is essential to develop strategies that enhance their chemical stability, biodegradability, and \u003cem\u003ein vivo\u003c/em\u003e compatibility. Surface modification has emerged as a crucial approach to improve the performance of MNPs as drug carriers (Rahimkhoei et al. \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Although Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e MNPs inherently possess a hydrophobic surface, clinical applications require them to be rendered hydrophilic and biocompatible. Surface coatings not only prevent particle aggregation but also enhance overall stability (Yingjie Yu et al. \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Common modifications include SiO\u003csub\u003e2\u003c/sub\u003e, organic molecules, proteins, and polymers (Zhou et al. \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). In particular, polymeric coatings facilitate the generation of hydrophilic nanostructures and present reactive functional groups that enhance drug conjugation efficiency while concurrently mitigating NP aggregation (Beach et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2024\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe incorporation of magnetic nanoparticles (MNPs) into polymer-based composites has unlocked new avenues in diverse fields, including biomedical engineering, tissue engineering, drug delivery systems (DDSs), as well as packaging and food processing, highlighting their versatile functional potential (Sharifianjazi et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Zefeng Wang et al. \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2022b\u003c/span\u003e). The selection of an appropriate polymer necessitates a comprehensive understanding of both its surface and bulk properties, as these intrinsic characteristics critically govern its functional performance (Venkataraman et al. \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). In drug delivery applications, both synthetic and natural polymers are utilized; however, natural polymers are often preferred due to their renewable sources, chemical versatility, biodegradability, and cost-effectiveness (Bijudas et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Prasad et al. \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Common examples include chitosan, albumin, alginate, collagen, gelatin, and dextran (Shaikh et al. \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Dextran (Dex), a natural polysaccharide composed of D-glucose units, is mainly produced by \u003cem\u003eLeuconostoc mesenteroides\u003c/em\u003e through fermentation (Zuo et al. \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Its backbone consists primarily of α-(1\u0026rarr;6) glycosidic linkages, with side branches connected \u003cem\u003evia\u003c/em\u003e α-(1\u0026rarr;3) or α-(1\u0026rarr;4) bonds (Yang et al. \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). This branched architecture imparts high water solubility, enabling efficient drug encapsulation and transport (Yifan Liu et al. \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2024b\u003c/span\u003e). Moreover, the abundance of functional groups in dextran allows for facile chemical modification and conjugation with ligands or nanoparticles, while also enhancing drug circulation time and targeted delivery to specific tissues (Petrovici et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Ramasundaram et al. \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOcta-amino propyl polyhedral oligomeric silsesquioxane (OA-POSS) represents a class of hybrid inorganic\u0026ndash;organic nanostructures consisting of a silica-like (Si\u0026ndash;O\u0026ndash;Si) cage functionalized with tunable organic substituents (Liang et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Loman-Cortes et al. \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Due to its highly ordered cage-like architecture, OA-POSS functions as a multifunctional nanomolecular platform enabling efficient drug encapsulation, protection, and controlled release (Chang et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e MNPs coated with natural polymers, despite their numerous advantages, also exhibit certain drawbacks such as immune system activation and inflammation, accumulation in organs, nonspecific binding, and irregular drug degradation and release within the body (Nordin et al. \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). These limitations can be effectively mitigated through surface modification with OA-POSS (Shang et al. \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2025\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe primary aim of this study is to design and fabricate core\u0026ndash;shell drug bio-nanocomposites engineered to respond to pH variations and externally applied magnetic fields, enabling controlled and targeted therapeutic delivery. Initially, Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex nanocomposites were synthesized, and the Dex coating on the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e surface was subsequently oxidized to its dialdehyde form (Dex-DA) using sodium periodate. To enhance drug-loading capacity and achieve a more controlled release behavior, the surface of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@ SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA was further functionalized with OA-POSS by means of a reversible Schiff-base condensation reaction. Subsequently, the anticancer drug DOX was loaded onto the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS bio-nanocomposite \u003cem\u003evia\u003c/em\u003e hydrogen bonding and electrostatic interactions. The drug release profile, release kinetics, and \u003cem\u003ein vitro\u003c/em\u003e cytotoxicity (MTT assay) were systematically evaluated. It is proposed that the imine bonds incorporated within the NC, owing to their stability at physiological pH and selective cleavage under mildly acidic conditions, can effectively mitigate the initial burst release and substantially extend the drug release profile. Overall, the obtained results suggest that Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX can serve as an efficient and stimuli-responsive DDS for potential cancer therapy applications.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"2. Experimental section","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Materials and chemicals\u003c/h2\u003e \u003cp\u003eDextran (Dex, average molecular weight 500,000 Da, relative viscosity 25\u0026ndash;40%, 1% solution in H\u003csub\u003e2\u003c/sub\u003eO at 25\u0026deg;C, purity\u0026thinsp;\u0026ge;\u0026thinsp;99.0% (was purchased from Nippon Sourced Paper Chemicals (Japan). Iron (III) chloride hexahydrate (FeCl\u003csub\u003e3\u003c/sub\u003e.6H\u003csub\u003e2\u003c/sub\u003eO, 98% Purity, Sigma Aldrich), Iron (II) chloride tetrahydrate (FeCl\u003csub\u003e2\u003c/sub\u003e\u0026middot;4H\u003csub\u003e2\u003c/sub\u003eO, 98% Purity, Sigma Aldrich), Sodium periodate (NaIO\u003csub\u003e4\u003c/sub\u003e, 99% Purity, Sigma Aldrich), 3-aminopropyl trimethoxy silane (APTES, 97% Purity, Sigma Aldrich), Ammonium hydroxide (NH\u003csub\u003e4\u003c/sub\u003eOH, 25% w/w, Sigma Aldrich), Methanol (CH\u003csub\u003e3\u003c/sub\u003eOH, \u0026ge;\u0026thinsp;99.8% Purity, Sigma Aldrich), Hydrochloric acid (HCl, 37% w/w, Sigma Aldrich), Ethylene glycol (C\u003csub\u003e2\u003c/sub\u003eH\u003csub\u003e6\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e, \u0026ge;\u0026thinsp;99% Purity, Sigma Aldrich), Ethanol (C\u003csub\u003e2\u003c/sub\u003eH\u003csub\u003e5\u003c/sub\u003eOH, \u0026ge;\u0026thinsp;99.8% Purity, Sigma Aldrich), Buffers: sodium acetate buffer (SAB, pH 5), phosphate-buffered saline (PBS, pH 7.4), and deionized water (H\u003csub\u003e2\u003c/sub\u003eO) were utilized throughout the study. The deionized water was freshly prepared in the laboratory prior to use. All other chemicals were obtained from Merck and used as received without any further purification. Doxorubicin hydrochloride (DOX) was sourced from Sobhan Pharmaceuticals Co. (Iran) and utilized directly in its supplied form, without undergoing any additional purification or modification.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Physical Characterization\u003c/h2\u003e \u003cp\u003eUltraviolet visible (UV\u0026ndash;Vis) absorption spectra of the samples were measured using a Shimadzu UV-1700 spectrophotometer to assess their optical properties. Fourier transform infrared (FT-IR) spectra were recorded at 25\u0026deg;C on a Bruker Aquinox 55 spectrometer, covering the spectral range from 400 to 4000 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. The magnetic characteristics of the core\u0026ndash;shell magnetic nanoparticles were evaluated with a Lakeshore Model 7410 vibrating sample magnetometer (VSM). Structural analysis was carried out through X-ray diffraction (XRD) using a Bruker D8 diffractometer, with scans performed in the 2θ range of 10\u0026deg;\u0026ndash;70\u0026deg;. The surface morphology of the NPs was examined via scanning electron microscopy (SEM) using a TESCAN MIRA instrument (working distance: 3.22 mm, field of view: 2.54 \u0026micro;m, magnification: 50,000\u0026times;). Elemental composition was assessed by energy-dispersive X-ray spectroscopy (EDX). Additionally, the hydrodynamic size distribution and zeta potential of the synthesized NPs were determined using dynamic light scattering (DLS) measurements (Malvern Instruments).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Preparation of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003e2.3.1. Synthesis of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e\u003c/h2\u003e \u003cp\u003eFe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e MNPs were synthesized via a modified co-precipitation and St\u0026ouml;ber process. Under a nitrogen atmosphere, FeCl\u003csub\u003e2\u003c/sub\u003e\u0026middot;4H\u003csub\u003e2\u003c/sub\u003eO (3.96 g, 20 mmol) and FeCl\u003csub\u003e3\u003c/sub\u003e\u0026middot;6H\u003csub\u003e2\u003c/sub\u003eO (10.82 g, 40 mmol) were dissolved in 320 mL of deionized water, followed by the slow addition of 40 mL NH\u003csub\u003e4\u003c/sub\u003eOH (25%) and stirring at 60\u0026deg;C for 8 h to yield Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e NPs, which were magnetically separated and washed thoroughly. Subsequently, 2 g of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e was dispersed in an ethanol/deionized water mixture (160 mL: 24 mL), and 4 mL of NH\u003csub\u003e4\u003c/sub\u003eOH (25%) and 4 mL of TEOS were added. The mixture was stirred at room temperature (25\u0026deg;C) for 12 h, and the obtained Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e NPs were collected magnetically, washed with deionized water, and dried for further use (Mohammadzadeh et al. \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2024b\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e2.3.2. Synthesis of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA\u003c/h2\u003e \u003cp\u003eFor the synthesis of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA NPs, initially, 50 mg of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e NPs were dispersed in 20 mL of deionized water by ultrasonication for 10 min to ensure a uniform suspension. Subsequently, 100 mg of dextran was added, and the suspension was gently stirred at 25\u0026deg;C for 12 h to achieve uniform coating of the polymer onto the NP surface. The resulting Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dextran NPs were separated using an external magnetic field and rinsed thrice with deionized water to remove residual, unbound dextran. For oxidation, the dextran-coated NPs were redispersed in 10 mL of acetate buffer (0.1 M, pH 5.0), and 10 mL of freshly prepared sodium periodate solution (10 mM, \u0026asymp;\u0026thinsp;21 mg NaIO\u003csub\u003e4\u003c/sub\u003e) was added dropwise under gentle stirring. The reaction was carried out in the dark at 4\u0026deg;C for 1 h to convert vicinal diols to dialdehyde groups. To quench residual periodate, 100 \u0026micro;L of ethylene glycol was added, and the mixture was stirred for 15 min. Dialdehyde-modified NPs were subsequently magnetically separated, thoroughly rinsed with deionized water, and preserved at 4\u0026deg;C (Guo et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Shokri et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003e2.3.3. Synthesis of OA-POSS\u003c/h2\u003e \u003cp\u003eOA-POSS was prepared through the hydrolytic condensation of APTES under acidic conditions, as illustrated in Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In summary, methanol (180 mL) and concentrated hydrochloric acid (15 mL, 35\u0026ndash;37%) were introduced into a 500 mL two-neck round-bottom flask equipped with a reflux condenser and a magnetic stirrer. APTES (7.5 mL, 30 mmol) was then added dropwise to the mixture at 60\u0026deg;C under continuous stirring. After complete addition, the reaction temperature was raised to 90\u0026deg;C, and the mixture was refluxed for 16 h. The resulting solution was cooled to 25\u0026deg;C and added dropwise into THF, leading to the formation of a white OA-POSS precipitate. The precipitate was collected, washed several times with THF, and dried under vacuum at 40\u0026deg;C for 24 h (Arsalani et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003e2.3.4. Synthesis of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS\u003c/h2\u003e \u003cp\u003eFe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS NPs were obtained by forming a Schiff-base imine reaction between the aldehyde groups present on Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA and the primary amine groups of OA-POSS. To begin, 0.2 g of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA was dispersed in 10 mL of distilled water under continuous mechanical stirring to obtain a homogeneous and stable colloidal suspension. In a separate container, 0.6 g of OA-POSS was dissolved in 15 mL of distilled water. The OA-POSS solution was then slowly added to the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA suspension, after which the pH of the reaction mixture was adjusted to approximately 7.4. The mixture was stirred at 25\u0026deg;C for 2 h, enabling the covalent attachment of OA-POSS to the NP surface. Finally, the modified NPs were collected using an external magnetic field, thoroughly washed with distilled water to remove any unattached components, and dried under vacuum at 25\u0026deg;C to obtain a clean and stable solid product (Mohammadzadeh et al. \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2024a\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e2.3.5. DOX loading in Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex and Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS\u003c/h2\u003e \u003cp\u003eFor DOX loading, 100 mg of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS and Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA were each mixed with 10 mg of DOX (2 mg/mL) in PBS (pH 7.4) and gently stirred for 30 min to obtain uniform suspensions. The mixtures were then incubated at 25\u0026deg;C with mild agitation in the dark for 72 h to ensure effective incorporation of DOX into the nanocarrier matrices. After the loading process, the DOX loaded NCs were separated using an external magnetic field and thoroughly washed with PBS (pH 7.4) to remove any unbound DOX. The purified nanocarriers were air-dried at 25\u0026deg;C. The concentration of unencapsulated DOX in the supernatants was measured utilizing UV\u0026ndash;Vis spectrophotometry at 480 nm, and the drug loading efficiency (DLE) and drug encapsulation efficiency (DEE) were calculated using Equations (1) and (2) (Javanbakht and Mohammadi \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Sanson et al. \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2010\u003c/span\u003e).\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\:DEE\\left(\\%\\right)=\\:\\frac{Mass\\:of\\:DOX\\:incorporated\\:into\\:the\\:nanocarriers}{Mass\\:of\\:DOX\\:added\\:to\\:the\\:systems\\:at\\:the\\:beginning}\\times\\:100\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\left(1\\right)$$\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Equb\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equb\" name=\"EquationSource\"\u003e\n$$\\:DLE\\left(\\%\\right)=\\frac{Mass\\:of\\:DOX\\:incorporated\\:into\\:the\\:nanocarriers}{Total\\:mass\\:of\\:the\\:DOX-loaded\\:nanocarriers}\\times\\:100\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\left(2\\right)$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e2.4. \u003cem\u003eIn vitro\u003c/em\u003e DOX release\u003c/h2\u003e \u003cp\u003eTo assess the DOX release behavior, 10 mg of the DOX-loaded nanocarriers (Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS) were suspended in 10 mL of PBS and SAB, respectively. The samples were incubated at 37\u0026deg;C under gentle shaking. At predetermined time intervals, 2 mL of the release medium was withdrawn and immediately replaced with an equal volume of fresh buffer to maintain sink conditions. The concentration of the released DOX in the collected samples was quantified using UV\u0026ndash;Vis spectroscopy at 480 nm, based on a previously established calibration curve under identical measurement conditions. The cumulative release percentage was calculated using Eq.\u0026nbsp;3. All experiments were conducted in triplicate to ensure reproducibility (Fathi and Mohammadi \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Javanbakht et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003cdiv id=\"Equc\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equc\" name=\"EquationSource\"\u003e\n$$\\:DOX\\:release\\:\\left(\\%\\right)=\\frac{Cumulative\\:DOXreleased\\:\\:\\left(mg\\right)}{Initial\\:DOXloaded\\:\\:\\left(mg\\right)}\\times\\:100\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\:\\left(3\\right)$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Storage stability and Colloidal stability study\u003c/h2\u003e \u003cp\u003eThe storage stability of the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX nanocomposite was systematically investigated, considering the physicochemical characteristics of the nanoparticles, the functional properties of the surface coatings, and the molecular sensitivity of DOX. To evaluate storage stability within the nanocarrier system, Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS nanocarriers were synthesized, loaded with DOX, and subsequently stored under controlled environmental conditions (5, 25, 50, and 100\u0026deg;C) for seven days in both dark and sunlight-exposed settings. Following the storage period, the release behavior of DOX was assessed at pH 5 and 41\u0026deg;C (Foroutan et al. \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2025c\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe colloidal stability of the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX nanocomposite under physiological conditions (pH 7.4) was systematically investigated. The nanocomposite was dispersed in 3 mL of PBS (pH 7.4) and incubated at 37\u0026deg;C for 7 days. Changes in hydrodynamic diameter were determined by dynamic light scattering (DLS) at predetermined time intervals to evaluate the stability of the dispersion under physiological conditions (Silva-Neto et al. \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2025\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e\u003cb\u003e2.6. Cytotoxicity study\u003c/b\u003e\u003c/h2\u003e \u003cp\u003eThe cytotoxicity of DOX-loaded nanocarriers, including Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX, Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS, and free DOX, was evaluated using the MTT assay. A549 cells were seeded in 96-well plates at a density of 8,000\u0026ndash;10,000 cells per well in 200 \u0026micro;L of culture medium and incubated overnight at 37\u0026deg;C. Cells were then treated with different concentrations of the samples and incubated for 48 h under dark or CO\u003csub\u003e2\u003c/sub\u003e-controlled conditions. For biocompatibility evaluation, cells were exposed to the corresponding blank nanocarriers. After incubation, the medium was replaced with fresh medium containing 20 \u0026micro;L of MTT solution (5 mg/mL) and incubated for 3\u0026ndash;4 h at 37\u0026deg;C to allow formazan formation. Finally, 200 \u0026micro;L of DMSO was added to dissolve the formazan crystals, and the absorbance was measured at 570 nm using a microplate reader. All assays were carried out in triplicate to validate the consistency and reproducibility of the data (Karimi and Namazi \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Naik et al. \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e2.7. DAPI staining\u003c/h2\u003e \u003cp\u003eTo further assess the therapeutic efficacy and potential biomedical applicability of the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX nanocomposite, its cellular internalization behavior was systematically evaluated in comparison with free DOX using fluorescence microscopy. A549 cells were cultured in 24-well plates and treated with either the DOX-loaded nanocomposite or free DOX at concentrations corresponding to the IC\u003csub\u003e50\u003c/sub\u003e values obtained from the MTT assay. After 48 h incubation at 37\u0026deg;C under standard cell culture conditions, the cells were thoroughly rinsed with phosphate-buffered saline (PBS) to eliminate residual extracellular compounds and subsequently fixed with 4% paraformaldehyde for 15 min at room temperature. Nuclear staining was performed using DAPI under light-protected conditions. Fluorescence images were then acquired to visualize intracellular drug localization and distribution, thereby providing qualitative insight into the cellular uptake efficiency of the nanocomposite system (Javanbakht and Mohammadi \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2025\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e2.8. Statistical analysis\u003c/h2\u003e \u003cp\u003eStatistical significance was determined using one-way analysis of variance (ANOVA) followed by Tukey\u0026rsquo;s post-hoc test. All analyses were performed using GraphPad Prism software (version 9.0.0). Data are expressed as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results and discussion","content":"\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e3.1. FT-IR analysis\u003c/h2\u003e \u003cp\u003eFT-IR spectroscopy was employed to investigate the functional groups of the synthesized materials, as depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e spectrum, distinct absorption bands appear near 555 cm⁻\u0026sup1; and 3392 cm⁻\u0026sup1;, which can be assigned to the Fe\u0026ndash;O stretching mode of the spinel structure and the O\u0026ndash;H stretching vibrations of surface hydroxyl groups, respectively (Foroutan et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2025b\u003c/span\u003e; Bochong Wang et al. \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2022a\u003c/span\u003e). In Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb, a strong band appears in the range of 1080\u0026ndash;1100 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, which is attributed to the asymmetric stretching vibrations of Si\u0026ndash;O\u0026ndash;Si bonds (Barutiak et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). This characteristic band confirms the formation of the silica network and indicates the successful coating of the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e NPs with the SiO\u003csub\u003e2\u003c/sub\u003e layer. In Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, the appearance of a peak around 1620 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, corresponding to C\u0026ndash;O stretching vibrations, along with the retention of characteristic peaks of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e NPs, provides clear evidence for the successful coating of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e with Dex (Mokhtari et al. \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed and e display a weak absorption band around 1718 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, corresponding to C\u0026thinsp;=\u0026thinsp;O and C\u0026thinsp;=\u0026thinsp;N stretching vibrations, which confirms the presence of aldehyde and imine functional groups in Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex and Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ef, the absorption bands located at around 3438 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and 1612 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e are attributed to the stretching and bending vibrations of \u0026ndash;NH\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e+\u003c/sup\u003e groups, respectively. Furthermore, the distinct peak observed at 1124 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, corresponding to the asymmetric stretching vibration of Si\u0026ndash;O\u0026ndash;Si bonds, confirms the well-defined formation of the Si\u0026ndash;O\u0026ndash;Si network, indicating the successful synthesis of OA\u0026ndash;POSS (Gohari et al. \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e3.2. VSM and XRD analyses\u003c/h2\u003e \u003cp\u003eThe XRD profiles of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e, Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex, and Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS NPs are illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA. As shown, the characteristic diffraction peaks appearing at 2θ values of 30.6, 35.4, 43.5, 53.8, 57.6, and 62.7 degrees are associated with the (220), (311), (420), (422), (511), and (440) crystallographic planes of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e. These diffraction peaks exhibit excellent agreement with the standard Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e reference pattern, thereby substantiating the preservation of the spinel crystal structure in the synthesized NPs. Following the surface modification of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e NPs with SiO\u003csub\u003e2\u003c/sub\u003e and Dextran, a broad diffraction band becomes evident at 2θ\u0026thinsp;\u0026asymp;\u0026thinsp;20\u0026ndash;25\u0026deg;, which is characteristic of the presence of an amorphous silica coating surrounding the magnetic core (Kutluay et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Patil et al. \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). In the final bio-nanocomposite, Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex\u0026ndash;DA@OA-POSS (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec), this amorphous signal becomes substantially more pronounced, appearing as a stronger and broader amorphous halo region within the 15\u0026ndash;30\u0026deg; range. The intensified amorphous background arises from the introduction of OA-POSS and DA-modified Dextran, both contributing non-crystalline components to the overall structure. The progressive enhancement of the amorphous region, together with the persistent and well-defined diffraction peaks of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e, confirms that each functional layer has been successfully incorporated while preserving the crystalline spinel structure of the magnetite core. This XRD behavior provides clear evidence of effective sequential surface modification without any detrimental impact on the core crystallinity (Jia et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBased on the obtained magnetization curves (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), the saturation magnetization values of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO₂ and Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS were determined to be 54 and 19 emu g⁻\u0026sup1;, respectively. The marked reduction in magnetic intensity observed for Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS is attributed to the presence of the non-magnetic Dex and OA-POSS layers coating the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e NPs, which diminishes the overall contribution of the magnetic core. Following their potential accumulation at the diseased site, exposure to an alternating magnetic field could, in principle, enable localized heat generation through magnetic hyperthermia. This thermal stimulus may potentially facilitate the release of therapeutics from thermoresponsive matrices or induce structural perturbations of the NC, thereby promoting on-demand drug liberation at the target location (Lucaciu \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). In addition to hyperthermia, magnetically induced drug release might also arise from the mechanical oscillation of MNPs under a pulsed magnetic field. While these mechanisms highlight the system\u0026rsquo;s theoretical potential, experimental validation under magnetic field exposure remains to be conducted. Such oscillatory motion can compromise the integrity of lipid membranes, ultimately facilitating intracellular release of the encapsulated agents. The characteristic S-shaped VSM profiles further confirm the superparamagnetic nature of the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS NPs and underscore their capacity for spatially controlled drug release in response to an external magnetic field (Dwivedi and Dwivedi \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Mohammadzadeh et al. \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2024a\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e3.3. DLS and SEM analyses\u003c/h2\u003e \u003cp\u003eIn the SEM images, the sample exhibits a distinctly rough, heterogeneous, and highly aggregated morphology, which is typical of hybrid organic\u0026ndash;inorganic nanocomposites. The presence of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e is confirmed by the ultrafine granular domains and clusters of spherical nanoparticles distributed throughout the structure. Such agglomerated assemblies arise from strong interparticle magnetic interactions that promote the formation of dense magnetic clusters (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea). The absence of individually dispersed NPs, along with the complete encapsulation of these magnetic clusters, indicates the successful formation of a continuous shell composed of SiO\u003csub\u003e2\u003c/sub\u003e and polymeric layers. The soft, amorphous, and smooth-edged surface regions correspond to the Dex-DA polymer coating, which typically produces a non-crystalline, cloud-like morphology after deposition on the silica surface. Moreover, the nanoscale protrusions and nodular surface roughness, observed as fine granular elevations, are characteristic of materials containing POSS units (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). The cage-like silsesquioxane framework of OA-POSS is known to impart this granular nano-roughness to hybrid nanocomposites (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec). The concurrent presence of these morphological signatures, namely the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e magnetic clusters, the polymer rich Dex-DA surface, and the nanoscale granular features associated with OA-POSS, strongly supports the successful integration of all components within the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS NC. Collectively, these structural observations provide compelling evidence for the proper assembly of the intended multilayer nanoplatform, confirming its suitability for targeted drug delivery applications (Chang et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Jia et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe mean hydrodynamic diameters of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex and Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS nanocomposites were quantitatively analyzed by DLS, yielding values of approximately 183 nm and 197 nm, respectively, as illustrated in Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ee and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed. NPs within the 100\u0026ndash;200 nm size range are widely recognized as optimal dimensions for DDSs due to their ability to evade rapid renal clearance and minimize recognition and uptake by the reticuloendothelial system (RES). This size range also facilitates enhanced passive targeting \u003cem\u003evia\u003c/em\u003e the enhanced permeability and retention (EPR) effect, enabling accumulation in tumor tissues, particularly when combined with external magnetic guidance. Furthermore, the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS nanocomposites exhibited a positive zeta potential averaging\u0026thinsp;+\u0026thinsp;19.6 mV, indicative of a positively charged nanoparticle surface. Such a surface charge contributes substantially to colloidal stability by preventing aggregation and promotes increased cellular uptake through electrostatic attraction to the negatively charged phospholipid membranes of cancer cells, thereby potentially improving intracellular delivery efficiency (Forest and Pourchez \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2017\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e3.4. \u003cem\u003eIn vitro\u003c/em\u003e DOX loading and release studies\u003c/h2\u003e \u003cp\u003eTo evaluate the efficacy of the synthesized nanocarriers in drug delivery, DOX was selected as a representative therapeutic agent to measure both drug encapsulation efficiency (DEE) and release kinetics. At a DOX to carrier weight ratio of 1:10, the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS nanocomposite exhibited a DEE of 95\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5%, while Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex achieved 80\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5% (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). It should be clarified that this value refers to DEE, which represents the amount of DOX encapsulated within the nanocarriers relative to the total amount of DOX used in the formulation. The significantly enhanced loading capacity observed in the OA-POSS functionalized nanocomposite is attributed to the presence of additional functional groups introduced by OA-POSS, which promote stronger intermolecular interactions with DOX molecules. These include hydrogen bonding, possible π\u0026ndash;π stacking interactions involving the aromatic rings of DOX, interactions with carbonyl groups within the polymeric matrix, as well as physical entrapment of the drug within the dense hybrid shell structure, collectively contributing to improved drug retention within the nanocarrier matrix. Release experiments conducted at pH 5 revealed that approximately 81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5% of DOX was released from Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS, whereas about 71\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5% was released from Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex over a period of 144 h. As illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA, the slower release profile observed for the OA-POSS modified NC is attributed to the imine bonds formed between OA-POSS and Dex-DA, which reinforce and stabilize the nanoparticle coating. These covalent bonds effectively suppress the initial burst release of DOX by reinforcing the structural integrity of the coating. Moreover, the three-dimensional structure of OA-POSS, along with its higher density of reactive groups, creates steric hindrance and additional physical barriers, which help regulate drug diffusion and promote a more sustained release. In contrast, Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex lacks these reinforcing covalent bonds and the associated stabilized multilayer shell, resulting in a more rapid drug release. Notably, the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX formulation exhibited the lowest DOX release at physiological pH (7.4) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB), a critical characteristic for systemic administration that potentially minimizes off-target toxicity and reduces adverse side effects associated with DOX treatment (Tao et al. \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2018\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFurthermore, the DOX release profiles obtained for the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS NC were fitted to four conventional kinetic models (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Analysis of the corresponding R\u0026sup2; coefficients demonstrated clear pH-dependent variations in release behavior. Such variations likely arise from pH-induced alterations in the physicochemical characteristics of the carrier matrix, which modify the predominant mechanism governing drug diffusion and release. The deviation of Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS at pH 5 from the Weibull model, and its better fit to the Higuchi model, is likely due to acid induced changes in the OA-POSS reinforced coating, including partial imine hydrolysis and increased porosity. These alterations shift the release mechanism toward a predominantly diffusion-controlled process, which aligns more closely with Higuchi kinetics under acidic conditions. Overall, the findings demonstrate that Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX nanocomposites provide a markedly prolonged release of DOX under acidic tumor-like conditions, underscoring their promise as a potent platform for targeted anticancer drug delivery.\u003c/p\u003e\u003cp\u003e\u003cimg 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\"\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec21\"\u003e\n \u003ch2\u003e3.5. DOX storage stability\u003c/h2\u003e\n \u003cp\u003eThe results presented in Fig. 5 demonstrate that exposure to elevated temperatures and light markedly decreases the storage stability of the nanocarriers, evidenced by reduced DOX release. This reduction is attributed to thermally and photochemically induced degradation of the drug, which compromises its retention within the nanocarrier matrix. Consistent with the Arrhenius equation (Eq. 4), the rate of degradation reactions escalates with increasing temperature, thereby accelerating DOX decomposition. Consequently, optimal storage conditions for maintaining nanocarrier integrity and drug stability are achieved in darkness at temperatures between 5 and 50°C. Furthermore, the colloidal stability of the final nanocomposite at pH 7.4 was evaluated over 7 days through hydrodynamic size measurements, and the results are provided in the Supporting Information (Fig. S1).\u003c/p\u003e\n \u003cdiv id=\"Equ1\"\u003e\n \u003cdiv format=\"TEX\" id=\"FileID_Equ1\" name=\"EquationSource\"\u003e$$\\:k=A{e}^{\\frac{{-E}_{a}}{RT}}$$\u003c/div\u003e\n \u003cdiv\u003e4\u003c/div\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec22\"\u003e\n \u003ch2\u003e3.6. MTT assay\u003c/h2\u003e\n \u003cp\u003eThe cytotoxicity and biocompatibility of the synthesized NCs were examined in A549 cells utilizing the MTT assay. As shown in Fig. 6, the unloaded Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS NCs exhibited excellent cytocompatibility, maintaining over 85% cell viability at a concentration of 0.5 µg/mL. This high level of cell survival suggests that the NC itself is inherently safe and well-tolerated by the cells, making it a suitable candidate for drug delivery applications. In contrast, when A549 cells were treated with DOX loaded Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS NCs, a significant reduction in cell viability was observed. Notably, the DOX loaded nanocomposite induced stronger cytotoxic effects than free DOX at the same drug concentration. This enhanced anticancer activity can be explained by the nanoscale size and surface characteristics of the carrier, which facilitate more efficient cellular uptake and increase intracellular accumulation of DOX. Consequently, the drug exerts its therapeutic effect more intensely than when administered in its free molecular form. Overall, these findings indicate that Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX represents a promising and effective nanoplatform for targeted anticancer drug delivery systems, combining biocompatibility with improved therapeutic performance.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec23\"\u003e\n \u003ch2\u003e3.7. Cellular apoptosis studies\u003c/h2\u003e\n \u003cp\u003eTo further confirm the results obtained from the MTT assay, fluorescence imaging was conducted on A549 cells after different treatments. DAPI staining was used as a nuclear fluorescent dye to observe apoptosis-related changes, since it binds strongly to DNA and allows clear visualization of nuclear morphology. Through this approach, features such as chromatin condensation and nuclear fragmentation could be detected. In this study, DAPI staining combined with fluorescence microscopy was applied to evaluate structural changes in the nuclei of treated A549 cells and to qualitatively assess the induction of apoptosis. To evaluate cytocompatibility and anticancer efficacy, A549 cells were treated with Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS, Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX, free DOX, and an untreated control group. Fluorescence images obtained following DAPI staining revealed a higher cell density in the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS treated group, confirming the favorable biocompatibility of the nanocomposites (Fig. 7b). Conversely, cells treated with Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX exhibited a markedly greater reduction in viability compared with those receiving free DOX (Fig. 7c, d). The improved cytotoxic performance can be attributed to the nanoscale dimensions of the synthesized nanoparticles, which enhance tumor tissue penetration and cellular internalization. Collectively, the DAPI staining results demonstrate that Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX efficiently induces apoptotic cell death, underscoring its potential as an effective drug delivery platform for cancer therapy.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. Conclusion","content":"\u003cp\u003eIn this work, a pH-responsive core\u0026ndash;shell magnetic nanocomposite incorporating OA-POSS, Dex, and Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e NPs \u003cem\u003evia\u003c/em\u003e a Schiff-base imine reaction was developed to improve targeted cancer treatment. The imine bond is responsible for the pH-responsive behavior, remaining stable at physiological pH and cleaving under acidic conditions to enable controlled DOX release. Introducing OA-POSS onto the NP surface significantly enhanced the DEE to approximately 95%, mainly due to the formation of hydrogen bonds and electrostatic attractions between DOX and the POSS groups. \u003cem\u003eIn vitro\u003c/em\u003e release studies confirmed a pronounced pH-responsive profile, with negligible DOX release (11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5%) at physiological pH 7.4, while acidic conditions at pH 5 induced a sustained release of 81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5% over 6 days. As a result, the initial burst release of the drug is minimized, which in turn reduces systemic toxicity and lowers the risk of adverse side effects. Based on cytotoxicity assessments against A549 cells, the optimal dose of this drug-loaded system is estimated to be approximately 1 \u0026micro;g/mL, corresponding to the determined IC\u003csub\u003e50\u003c/sub\u003e value. Additionally, \u003cem\u003ein vitro\u003c/em\u003e cytotoxicity assessments, along with DAPI staining, revealed that the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX nanocomposite exhibited markedly enhanced anticancer activity against A549 cells compared with free doxorubicin. This improved cytotoxicity is likely related to the small particle size of the nanocomposite, which enhances penetration into tumor tissues and increases cellular uptake of the drug. Altogether, these results show that the proposed nanosystem not only improves the therapeutic potential of DOX but also represents a promising platform for more accurate and effective cancer-targeted drug delivery.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eauthorship contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRamezan Ali Taheri\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e Formal analysis, writing\u0026mdash;review \u0026amp; editing. \u003cstrong\u003eAli Mohammadzadeh:\u003c/strong\u003e Data curation, Software, Conceptualization, Visualization, Investigation, Writing\u0026mdash;original draft, Project administration, Validation, Methodology. \u003cstrong\u003eReza Mohammadi:\u0026nbsp;\u003c/strong\u003eData curation. \u003cstrong\u003eRamin\u0026nbsp;Karimian\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e Formal analysis,\u0026nbsp;writing\u0026mdash;review \u0026amp; editing.\u0026nbsp;\u003cstrong\u003eMohammad Reza Khodabakhshi:\u0026nbsp;\u003c/strong\u003eResources, supervision, writing\u0026mdash;review \u0026amp; editing, validation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData will be made available on request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to express their sincere gratitude to all collaborators who contributed to this research. Their valuable assistance, insightful discussions, and technical support are greatly appreciated.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eArsalani N, Kazeminava F, Akbari A, Hamishehkar H, Jabbari E, Kafil HS (2019) Synthesis of polyhedral oligomeric silsesquioxane nano-crosslinked poly (ethylene glycol)‐based hybrid hydrogels for drug delivery and antibacterial activity. Polym Int 68(4):667\u0026ndash;674\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarutiak M, Zeleň\u0026aacute;kov\u0026aacute; A, Hrubovč\u0026aacute;k P, Nagy L, Szűcsov\u0026aacute; J, Fabriciov\u0026aacute; Ž., Beňov\u0026aacute; E, Kir\u0026aacute;ly N, Zeleň\u0026aacute;k V, Antošov\u0026aacute; A (2025) Enhanced efficiency of fe3o4@ sio2 with specific ligand layer in magnetic separation technique. Surfaces and Interfaces:107252\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeach MA, Nayanathara U, Gao Y, Zhang C, Xiong Y, Wang Y, Such GK (2024) Polymeric nanoparticles for drug delivery. Chem Rev 124(9):5505\u0026ndash;5616\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBijudas K, Megha S, Greeshma G, Reshma R, Jiju K (2025) Hyaluronic acid-coated zeolitic imidazolate framework (zif-67) for the targeted and ph-responsive drug delivery system. J Inorg Organomet Polym Mater :1\u0026ndash;11\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChang YK, Hao SJ, Wu FG (2024) Recent biomedical applications of functional materials based on polyhedral oligomeric silsesquioxane (poss). Small 20(48):2401762\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDwivedi R, Dwivedi RK (2025) A comprehensive review on conducting polymers for multifaceted applications. J Inorg Organomet Polym Mater :1\u0026ndash;39\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFathi R, Mohammadi R (2023) Preparation of ph-responsive magnetic nanocomposite hydrogels based on k-carrageenan/chitosan/silver nanoparticles: Antibacterial carrier for potential targeted anticancer drug delivery. Int J Biol Macromol 246:125546\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eForest V, Pourchez J (2017) Preferential binding of positive nanoparticles on cell membranes is due to electrostatic interactions: A too simplistic explanation that does not take into account the nanoparticle protein corona. Mater Sci Engineering: C 70:889\u0026ndash;896\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eForoutan R, Mohammadzadeh A, Mohammadi R, Javanbakht S (2025a) Carboxymethyl cellulose/hydroxyapatite/fe3o4 bio-nanocomposite hydrogel beads: An efficient oral ph-responsive carrier for doxorubicin delivery. Chem Pap :1\u0026ndash;10\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eForoutan R, Mohammadzadeh A, Mohammadi R, Javanbakht S (2025b) Carboxymethyl cellulose/hydroxyapatite/fe3o4 bio-nanocomposite hydrogel beads: An efficient oral ph-responsive carrier for doxorubicin delivery. Chem Pap 79(4):2461\u0026ndash;2470\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eForoutan R, Mohammadzadeh A, Javanbakht S, Mohammadi R, Ghorbani M (2025c) Alginate/magnetic hydroxyapatite bio-nanocomposite hydrogel bead as a ph-responsive oral drug carrier for potential colon cancer therapy. Results Chem 15:102177\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhasemi S, Karimzadeh M, Kafshboran HR (2025) Magnetically recoverable gold catalyst supported on pvim-grafted fe₃o₄@ cqd composite for efficient nitroarene reduction in water. J Organomet Chem :123941\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGohari G, Panahirad S, Mohammadi A, Kulak M, Dadpour MR, Lighvan ZM, Eftekhari-Sis SS, Szafert B, Fotopoulos S V (2023) Characterization of octa-aminopropyl polyhedral oligomeric silsesquioxanes (oa-poss) nanoparticles and their effect on sweet basil (ocimum basilicum l.) response to salinity stress. Plant Physiol Biochem 196:89\u0026ndash;102\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo H, Lei B, Yu J, Chen Y, Qian J (2021) Immobilization of lipase by dialdehyde cellulose crosslinked magnetic nanoparticles. Int J Biol Macromol 185:287\u0026ndash;296\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHosseinzadeh H, Vahdatkhah A, Javanbakht S, Mohammadi R (2025) Synthesis of ph-responsive hollow molecularly imprinted polymers for enhanced doxorubicin delivery in cancer therapy. J Pharm Sci :103993\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJavanbakht S, Nabi M, Shaabani A (2021) Graphene quantum dots-crosslinked gelatin via the efficient ugi four-component reaction: Safe photoluminescent implantable carriers for the ph-responsive delivery of doxorubicin. Materialia 20:101233\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJavanbakht S, Mohammadi R (2025) Chondroitin sulfate-decorated cupper-benzene dicarboxylate framework as an efficient passive and active targeting nanomedicine for anticancer methotrexate delivery. International Journal of Pharmaceutics: X:100403\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJia P, Cheng W, Lu J, Yin Z, Xu Z, Cheng L, Qiu Y, Qian L, Hu Y, Hu W (2021) Applications of go/oa-poss layer‐by‐layer self‐assembly nanocoating on flame retardancy and smoke suppression of flexible polyurethane foam. Polym Adv Technol 32(11):4516\u0026ndash;4530\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarimi S, Namazi H (2021) Fe3o4@ peg-coated dendrimer modified graphene oxide nanocomposite as a ph-sensitive drug carrier for targeted delivery of doxorubicin. J Alloys Compd 879:160426\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKutluay S, Horoz S, Şahin \u0026Ouml;, Ekinci A, Ece MŞ (2021) Highly improved solar cell efficiency of mn-doped amine groups‐functionalized magnetic fe3o4@ sio2 nanomaterial. Int J Energy Res 45(14):20176\u0026ndash;20185\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiang Y, Xu J, Ahmed N, Shi J, Wen M, Yan N (2024) Construction of biomass-based flame-retardant, antimicrobial and hydrophobic wood coatings with poss organic-inorganic nanoparticles. Eur Polymer J 219:113370\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLinders AN, Dias IB, L\u0026oacute;pez Fern\u0026aacute;ndez T, Tocchetti CG, Bomer N, Van der Meer P (2024) A review of the pathophysiological mechanisms of doxorubicin-induced cardiotoxicity and aging. npj Aging 10(1):9\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu B, Zhou H, Tan L, Siu KTH, Guan X-Y (2024a) Exploring treatment options in cancer: Tumor treatment strategies. Signal Transduct Target therapy 9(1):175\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Y, Liang Y, Yuhong J, Xin P, Han JL, Du Y, Yu X, Zhu R, Zhang M, Chen W (2024b) Advances in nanotechnology for enhancing the solubility and bioavailability of poorly soluble drugs. Drug design, development and therapy:1469\u0026ndash;1495\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLoman-Cortes P, Binte Huq T, Vivero-Escoto JL (2021) Use of polyhedral oligomeric silsesquioxane (poss) in drug delivery, photodynamic therapy and bioimaging. Molecules 26(21):6453\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLong H, Ryu S, Zheng X-L, Zhang L-S, Li L-Y, Zhang Z-S (2023) Peptide l1h9 derived from the interaction of structural human rhomboid family 1 and 80-kda subunit of ku antigen sensitizes breast cancer to chemoradiotherapy. Adv Compos Hybrid Mater 6(6):208\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLucaciu CM (2024) Magnetic nanomaterials for hyperthermia-based therapy, imaging, and drug delivery. MDPI, p 263\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohammadzadeh A, Javanbakht S, Mohammadi R (2024a) Magnetic alginate core-shell nanoparticles based on schiff-base imine bonding for ph-responsive doxorubicin delivery system. Colloids Surf A 697:134473\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohammadzadeh A, Javanbakht S, Mohammadi R, Kazeminava F (2024b) Ferrocene-functionalized magnetic core-shell nanoparticles based on hydrosilylation reaction for ph-responsive doxorubicin delivery system. Colloids Surf A 703:135201\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohammadzadeh A, Javanbakht S, Mohammadi R (2025) Encapsulation of nh2-mil-101 (fe) with dialdehyde starch through schiff-base imine: A development of a ph-responsive core-shell fluorescent nanocarrier for doxorubicin delivery. Carbohydr Polym Technol Appl 10:100794\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMokhtari F, Poladian M, Shamloo A (2024) A method for macromolecule transport to the spinal cord nervous system trauma with a combination of ultrasound and magnetic fields. Int J Nano Dimension, 15(1 (January 2024)).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNaik N, Adeyanju O, Samrot AV, Bhat P, Salmataj S (2023) Drug delivery through microneedles for improved permeability and efficacy: Fabrication, methodology and applications. Eng Sci 26:1065\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNgwu-Hyacinth O, Alford A, Rowe CS, Willoughby R, Mirbozorgi SA, Rothenberg SA, Jones J, Sajan A, Krishnasamy VP, Bolding M (2025) Ultrasmall superparamagnetic iron oxide nanoparticles as positive contrast agents in low‐field magnetic resonance imaging. Iradiology 3(5):372\u0026ndash;387\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNordin AH, Ahmad Z, Husna SMN, Ilyas RA, Azemi AK, Ismail N, Nordin ML, Ngadi N, Siti NH, Nabgan W (2023) The state of the art of natural polymer functionalized fe3o4 magnetic nanoparticle composites for drug delivery applications: A review. Gels 9(2):121\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatil PJ, Dong X, Usman M, Bhambore NR, Shah H, Zhang C, Li X (2023) Recent trends in metal-organic frameworks mediated lipase immobilization: A state‐of‐the‐art review. Food Saf Health 1(2):139\u0026ndash;169\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePetrovici AR, Pinteala M, Simionescu N (2023) Dextran formulations as effective delivery systems of therapeutic agents. Molecules 28(3):1086\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrasad RD, Prasad NR, Prasad RB, Prasad RY, Prasad SR, Gour M, Vaidya AK, Patil M, Patil S, Karmuse S (2023) A critical review on bio-mimetic synthesis of transition metal nanoparticles: Their biomedical applications in veterinary medicine. ES Food Agrofor 15:1027\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRahimkhoei V, Alzaidy AH, Abed MJ, Rashki S, Salavati-Niasari M (2024) Advances in inorganic nanoparticles-based drug delivery in targeted breast cancer theranostics. Adv Colloid Interface Sci 329:103204\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamasundaram S, Saravanakumar G, Sobha S, Oh TH (2022) Dextran sulfate nanocarriers: Design, strategies and biomedical applications. Int J Mol Sci 24(1):355\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSanson C, Schatz C, Le Meins J-F, Soum A, Th\u0026eacute;venot J, Garanger E, Lecommandoux S (2010) A simple method to achieve high doxorubicin loading in biodegradable polymersomes. J Controlled Release 147(3):428\u0026ndash;435\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShaikh MAJ, Alharbi KS, Almalki WH, Imam SS, Albratty M, Meraya AM, Alzarea SI, Kazmi I, Al-Abbasi FA, Afzal O (2022) Sodium alginate based drug delivery in management of breast cancer. Carbohydr Polym 292:119689\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShang J, Zhang S, Qiu X, Zhang J, Lin K, Xia D, Zhang L, Yang Y (2025) Recent advances in modification and application of polyhedral oligomeric silsesquioxane/polyurethane composites: A comprehensive review. Macromol Rapid Commun 46(19):e00337\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSharifianjazi F, Irani M, Esmaeilkhanian A, Bazli L, Asl MS, Jang HW, Kim SY, Ramakrishna S, Shokouhimehr M, Varma RS (2021) Polymer incorporated magnetic nanoparticles: Applications for magnetoresponsive targeted drug delivery. Mater Sci Engineering: B 272:115358\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShokri M, Mojtabavi S, Jafari-Nodoushan H, Vojdanitalab K, Golshani S, Jahandar H, Faramarzi MA (2022) Laccase-loaded magnetic dialdehyde inulin nanoparticles as an efficient heterogeneous natural polymer-based biocatalyst for removal and detoxification of ofloxacin. Biodegradation 33(5):489\u0026ndash;508\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSilva-Neto AF, de Carvalho Amaral AR, de Alencar Danda LJ, Chaves LL, Alves LDS, Soares M. F. d. L. R., Soares-Sobrinho JL (2025) Decoding excipients in lipid-based self-emulsifying drug delivery systems: Insights into physicochemical properties and therapeutic outcomes. International Journal of Pharmaceutics:126018\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTao Y, Liu S, Zhang Y, Chi Z, Xu J (2018) A ph-responsive polymer based on dynamic imine bonds as a drug delivery material with pseudo target release behavior. Polym Chem 9(7):878\u0026ndash;884\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTenchov R, Hughes KJ, Ganesan M, Iyer KA, Ralhan K, Lotti Diaz LM, Bird RE, Ivanov JM, Zhou QA (2025) Transforming medicine: Cutting-edge applications of nanoscale materials in drug delivery. ACS Nano 19(4):4011\u0026ndash;4038\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVagena I-A, Malapani C, Gatou M-A, Lagopati N, Pavlatou EA (2025) Enhancement of epr effect for passive tumor targeting: Current status and future perspectives. Appl Sci 15(6):3189\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan der Merwe L, Kaschula CH, Chellan P (2025) Organometallic conjugates of artesunate: Synthesis and evaluation of anticancer potential. J Organomet Chem :123804\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVenkataraman S, Hedrick JL, Ong ZY, Yang C, Ee PLR, Hammond PT, Yang YY (2011) The effects of polymeric nanostructure shape on drug delivery. Adv Drug Deliv Rev 63(14\u0026ndash;15):1228\u0026ndash;1246\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang B, Ji Y, Mu C, Huo Y, Xiang J, Nie A, Xue T, Zhai K, Liu Z, Wen F (2022a) Well-controlled core-shell structures based on fe3o4 nanospheres coated by polyaniline for highly efficient microwave absorption. Appl Surf Sci 591:153176\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Q, Chen J, Ling J, Zhao H, Ouyang X-k, Wang N (2024) Metal-polyphenol network coated photothermal nanocarriers for ph-activated drug delivery. Mater Today Chem 35:101892\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Z, Li R, Zhang J (2022b) On-demand drug delivery of triptolide and celastrol by poly (lactic-co-glycolic acid) nanoparticle/triglycerol monostearate-18 hydrogel composite for rheumatoid arthritis treatment. Adv Compos Hybrid Mater 5(4):2921\u0026ndash;2935\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang W, Su L, Wang L, Wu J, Chen S (2022) Alpha-glucanotransferase from the glycoside hydrolase family synthesizes α (1\u0026ndash;6)-linked products from starch: Features and synthesis pathways of the products. Trends Food Sci Technol 128:160\u0026ndash;172\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu H, Hao P, Si P, Wang B, Shen Q, Zhu H, Lin W, Hu Q (2024) A mn-based metal-organic framework mn-cpp for combined chemodynamic therapy and chemotherapy. J Organomet Chem 1019:123305\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu Y, Xu Q, He S, Xiong H, Zhang Q, Xu W, Ricotta V, Bai L, Zhang Q, Yu Z (2019) Recent advances in delivery of photosensitive metal-based drugs. Coord Chem Rev 387:154\u0026ndash;179\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou H, Li C, Zhang Y, Tu W, Li Q, Peng Y, Zhang Z, Zheng Z (2025) Nano-sio2/pvc composite material: A review on modification, preparation, properties, and applications. J Appl Polym Sci 142(42):e57605\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZuo X, Pan L, Zhang W, Zhu J, Qin Y, Xu X, Wang Q (2024) The discovery, molecular cloning, and characterization of dextransucrase lm dexa and its active truncated mutant from leuconostoc mesenteroides nn710. Molecules 29(13):3242\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Scheme 1","content":"\u003cp\u003eScheme 1 is available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"chemical-papers","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"chpa","sideBox":"Learn more about [Chemical Papers](http://link.springer.com/journal/11696)","snPcode":"11696","submissionUrl":"https://www.editorialmanager.com/CHPA/default.aspx","title":"Chemical Papers","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Octa-aminopropyl polyhedral oligomeric silsesquioxane, Schiff-base imine reaction, Dextran dialdehyde, pH-sensitive system","lastPublishedDoi":"10.21203/rs.3.rs-9419286/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9419286/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn this study, a pH-responsive drug delivery system (DDS) based on octa-aminopropyl polyhedral oligomeric silsesquioxane (OA-POSS), dextran (Dex), and magnetic nanoparticles (MNPs) was developed for potential cancer therapy applications. Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e NPs were initially synthesized and subsequently functionalized with dextran dialdehyde (Dex-DA) and OA-POSS through a Schiff-base imine reaction, yielding the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS nanocarrier (NC). Doxorubicin (DOX), used as a model anticancer agent, was successfully loaded onto the NC \u003cem\u003evia\u003c/em\u003e noncovalent physical interactions, achieving a high drug loading efficiency of approximately 95%. The synthesized NCs were characterized using FT-IR, FE-SEM, DLS, XRD, and VSM techniques. \u003cem\u003eIn vitro\u003c/em\u003e drug release studies demonstrated pronounced pH-responsive behavior. At physiological pH (7.4), less than 15% of DOX was released, whereas under acidic conditions (pH 5), approximately 81% of the drug was released over a period 6 days. Cytotoxicity assessments revealed that the blank Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS NCs were biocompatible with cell viability above 85%. In contrast, DOX-loaded NCs exhibited strong anticancer activity against A549 cells, with an IC\u003csub\u003e50\u003c/sub\u003e value of around 1 \u0026micro;g/mL, attributed to the controlled release of DOX. Overall, the Fe\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e@SiO\u003csub\u003e2\u003c/sub\u003e@Dex-DA@OA-POSS/DOX NC shows promising potential as a targeted and stimuli-responsive drug delivery platform for cancer treatment.\u003c/p\u003e","manuscriptTitle":"Octa-aminopropyl polyhedral oligomeric silsesquioxane-functionalized magnetic dextran nanoparticles via dynamic Schiff-base imine bonds for sustained doxorubicin release","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-29 23:34:20","doi":"10.21203/rs.3.rs-9419286/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-11T12:07:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-09T05:10:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"246921296172286439642538873419503395166","date":"2026-05-04T10:41:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"193276228061382203285093182656822765026","date":"2026-05-03T14:58:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-01T19:39:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"61567833120452572590811697087243609580","date":"2026-04-21T17:49:58+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-20T21:13:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-20T08:43:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-20T08:04:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"Chemical Papers","date":"2026-04-14T20:00:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"chemical-papers","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"chpa","sideBox":"Learn more about [Chemical Papers](http://link.springer.com/journal/11696)","snPcode":"11696","submissionUrl":"https://www.editorialmanager.com/CHPA/default.aspx","title":"Chemical Papers","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3dede85b-e1cf-4ec6-9a04-a853ec85b57d","owner":[],"postedDate":"April 29th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-11T12:07:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-09T05:10:20+00:00","index":26,"fulltext":""},{"type":"reviewerAgreed","content":"246921296172286439642538873419503395166","date":"2026-05-04T10:41:44+00:00","index":25,"fulltext":""},{"type":"reviewerAgreed","content":"193276228061382203285093182656822765026","date":"2026-05-03T14:58:21+00:00","index":24,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-01T19:39:55+00:00","index":18,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-11T12:51:47+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-29 23:34:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9419286","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9419286","identity":"rs-9419286","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}