Phototherapy via modulation of β-amyloid in combating Alzheimer’s Disease

Phototherapy via modulation of β-amyloid in combating Alzheimer’s Disease | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Aggregate This is a preprint and has not been peer reviewed. Data may be preliminary. 3 January 2025 V1 Latest version Share on Phototherapy via modulation of β-amyloid in combating Alzheimer’s Disease Authors : Yunhua Zhang , Chengyuan Qian , Yuncong Chen 0000-0002-8406-4866 [email protected] , Weijiang He , and Zijian Guo Authors Info & Affiliations https://doi.org/10.22541/au.173586974.46692192/v1 Published Aggregate Version of record Peer review timeline 611 views 328 downloads Contents Abstract Phototherapy via modulation of β-amyloid in combating Alzheimer’s Disease Photodynamic therapy 3.2 Metal nanoparticles 3.3 Carbon Dots nanomaterials 3.4 Polymeric nanoparticles 3.5 Upconversion nanoparticles (UCNPs) 3.6 Two-Dimensional Nanomaterials Photothermal therapy 4.2 Inorganic photothermal nanoparticles Photopharmacology Photobiomodulation Summary and perspectives Acknowledgements References Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Alzheimer’s disease (AD) is one of the most prevalent forms of neurodegenerative diseases. Although some controversy exists, β-amyloid peptide (Aβ) is recognized to play an essential role in the pathophysiology of AD. The Aβ species are known to exist in various forms, including soluble monomers, oligomers, and insoluble aggregates. Despite extensive efforts to regulate Aβ aggregation, no successful medications have been developed to date. Among the various strategies for AD treatment, phototherapy, including photodynamic therapy (PDT), photothermal therapy (PTT), photopharmacology, and photobiomodulation (PBM) have attracted increased attention because of the spatiotemporal controllability. Representative examples of PDT, PTT, photopharmacology and PBM are discussed in terms of inhibitory mechanism, the unique properties of materials, and the design of phototherapy modulators. The major challenges of phototherapy against AD are addressed and the promising prospects are proposed. It is concluded that the noninvasive light-assisted approaches will become a promising strategy for intensifying the modulation of Aβ aggregation or promoting Aβ clearance and thus facilitating AD treatment. Phototherapy via modulation of β-amyloid in combating Alzheimer’s Disease Yunhua Zhang 1 †, Chengyuan Qian 3 †, Yuncong Chen 1,2,4* , Weijiang He 1,2* and Zijian Guo 1,2,* 1 State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing 210023, China. 2 Nanchuang (Jiangsu) Institute of Chemistry and Health, Nanjing 210000, China. 3 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China. 4 Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210008, China. †Yunhua Zhang and Chengyuan Qian contributed equally to this manuscript. **Correspondence: [email protected] ; [email protected] ; [email protected] . Abstract Alzheimer’s disease (AD) is one of the most prevalent forms of neurodegenerative diseases. Although some controversy exists, β-amyloid peptide (Aβ) is recognized to play an essential role in the pathophysiology of AD. The Aβ species are known to exist in various forms, including soluble monomers, oligomers, and insoluble aggregates. Despite extensive efforts to regulate Aβ aggregation, no successful medications have been developed to date. Among the various strategies for AD treatment, phototherapy, including photodynamic therapy (PDT), photothermal therapy (PTT), photopharmacology, and photobiomodulation (PBM) have attracted increased attention because of the spatiotemporal controllability. Representative examples of PDT, PTT, photopharmacology and PBM are discussed in terms of inhibitory mechanism, the unique properties of materials, and the design of phototherapy modulators. The major challenges of phototherapy against AD are addressed and the promising prospects are proposed. It is concluded that the noninvasive light-assisted approaches will become a promising strategy for intensifying the modulation of Aβ aggregation or promoting Aβ clearance and thus facilitating AD treatment. Introduction Alzheimer’s disease (AD), the most common form of dementia, affects over 50 million individuals aged 65 and older globally, imposing significant burdens on healthcare systems. This neurodegenerative condition is clinically characterized by progressive and irreversible memory loss and is associated with various pathological features, including Aβ plaque accumulation, synaptic and neuronal loss, intracellular neurofibrillary tangles, and disrupted metal-ion homeostasis. While the precise molecular mechanisms of AD remain unclear, the long-recognized link between Aβ aggregates and neurodegeneration has positioned Aβ as a critical therapeutic target. However, decades of unsuccessful drug development targeting Aβ have raised doubts about the viability of this approach [1–3]. The Aβ is generated through the amyloidogenic pathway, wherein amyloid precursor protein (APP) undergoes proteolytic cleavage by β-secretase and γ-secretase, producing Aβ1-40 (90%) and Aβ1-42 (9%) [4]. During aggregation, hydrophobic residues within the Aβ sequence (Leu17–Ala21) cluster to minimize water exposure. This clustering fosters non-covalent interactions, including van der Waals forces and hydrophobic bonds, driven primarily by the hydrophobic C-terminal region, which promotes Aβ aggregation [4] (Scheme 1). The resulting oligomers and plaques trigger a cascade of events, such as neuronal dysfunction, inflammation, and neurodegeneration, forming the cornerstone of current theories on AD pathogenesis. Recent FDA approvals of anti-Aβ antibody therapies—aducanumab (Aduhelm), lecanemab (Leqembi), and donanemab (Kisunla)—have reignited interest in targeting Aβ. These treatments effectively lower brain Aβ levels, slowing disease progression and reinforcing the validity of Aβ as a therapeutic target. Strategies aimed at inhibiting Aβ aggregation or degrading aggregates [5] hold significant promise for AD treatment and prevention [6]. Nevertheless, clinical challenges persist, including poor targeting specificity, high toxicity, and adverse side effects [7,8]. This underscores the urgent need for novel therapeutic approaches or modalities to improve outcomes for clinically challenging AD cases. Scheme 1. Schematic representation of production of the Aβ1-40 and Aβ1-42 via proteolytic cleavage of APP and the Aβ aggregation pathway’s sigmoidal curve shows three stages (lag, elongation, and plateau) Phototherapy has gained attention as a minimally invasive alternative to traditional cancer treatments like chemotherapy, radiotherapy, and surgery, offering effective cancer cell elimination and improved clinical outcomes [9–13]. Its benefits include non-invasiveness, safety, selectivity, and a lack of drug resistance. Notably, phototherapy also shows significant potential in addressing AD. In PDT, light activation excites a photosensitizer to its triplet state, enabling interactions with oxygen or nearby molecules to produce reactive oxygen species. These species play a role in inhibiting Aβ aggregation or degrading Aβ fibrils [14,15]. In PTT, a photothermal agent absorbs light, typically in the near-infrared (NIR) range, and releases heat upon returning to its ground state, thereby modulating Aβ assembly [16]. Photopharmacology employs photoswitchable ligands that undergo isomerization under specific wavelengths of light, acting as reversible ”switches” between inactive and active photoisomers. This mechanism enables precise temporal control over receptor activation or the aggregation behavior of amyloid proteins [17]. PBM influences cerebral blood flow, brain energy metabolism, and antioxidant defenses to counteract AD progression [18–21]. While the mechanisms underlying these phototherapies differ, light serves as a crucial element, directly influencing their therapeutic outcomes. Here, we will describe recent progresses in photo-induced modulation of Aβ self-assembly and degradation through the generation of localized heat, oxidative stress, molecular configuration transformation, and altering the brain microenvironment. First, we will overview different characteristics and performances of various photosensitizers, photothermal and photoisomerization platforms, highlighting their distinct characteristics and performances in inhibiting Aβ self-assembly and disassembling preformed aggregates under light exposure. Second, we will discuss the potential mechanisms of PBM therapies for promoting Aβ clearance and the associated therapeutic challenges. Finally, we will summarize the current issues and propose the prospects of photo-induced modulation of Aβ aggregation and clearance as a therapeutic strategy for phototherapy in AD (Scheme 2). Scheme 2. Schematic view of light-modulation of Aβ aggregation, highlighting four applications: PDT, PTT, Photopharmacology and PBM systems. Photodynamic therapy Photosensitizers have been extensively applied across diverse fields, including healthcare-such as biosensing, imaging, and PDT-and energy conversion, exemplified by dye-sensitized solar cells and photochemical water-splitting [22,23]. These applications leverage the unique photochemical properties of natural dyes like porphyrins and flavins, their derivatives, and synthetic photocatalysts. PDT, a noninvasive technique with excellent spatiotemporal precision and high efficiency, has been widely utilized to suppress Aβ aggregation or degrade Aβ fibrils [24,25]. During PDT, photosensitizers generate singlet oxygen (¹O₂), which facilitates the oxidation of Aβ proteins via photo-oxidation [26,27]. In this section, we describe light-triggered anti-aggregation of Aβ or Aβ degradation through photodynamic reactions using photosensitizers, such as molecular photosensitizers, metal nanoparticles, carbon-based nanomaterials, polymeric nanoparticles, up-conversion nanoparticles (UCNPs) and two-dimensional nanomaterials. 3.1 Molecular photosensitizers 3.1.1 Thioflavin-T derivatives Organic small molecule dyes are a promising photosensitizer which can be used in optical diagnosis and treatment because of their definite and easily modified chemical structure, good reproducibility and excellent biocompatibility [28]. In 2010, Goto and colleagues [29] investigated the impact of laser irradiation on Aβ fibrils using thioflavin-T (ThT) combined with total internal reflection fluorescence microscopy, and found that laser irradiation could disrupt preformed Aβ fibrils in a dose-dependent manner. (Figure 1a and 1b). It was also found that under 442 nm light irradiation, ThT, upon excitation, could produce singlet oxygen (¹O₂), which subsequently inhibited the growth of β2-microglobulin (β2-m) or degraded K3 fibrils. Notably, β2-m is a well-known immunoglobulin domain consisting of 99 amino acid residues and seven β-strands [30]. Intriguingly, low-dose irradiation during fibril formation yielded an opposite effect; partial fragmentation of the fibrils increased the number of active ends, thereby accelerating fibril propagation. This effect, described as ’explosive’ growth, highlights the dual potential of laser irradiation to either dismantle or facilitate fibril assembly, depending on the irradiation conditions (Figure 1c and 1d). Such findings provide a foundation for optimizing photodynamic interventions, where controlled modulation of fibril dynamics could be employed for either amyloid degradation or selective disruption during specific stages of fibril formation. Figure 1. a) Structure of ThT, 1 . b) Quantification of fibril propagation or degradation over time based on TIRFM imaging. c) Direct visualization of rapid fibril growth initiated from a single fibril. d) Intermittent laser exposure inducing disassembly of preformed fibrils. e) Chemical structures of photosensitizers TaSCAc ( 2 and 3 ) . f) Illustration of TaSCAc-mediated treatment for AD, where the catalyst selectively targets and oxidizes cross-β-sheet aggregates upon activation. g) AFM image of Aβ42 with 3 , incubated at 37°C under either non-irradiated conditions (‘native’) or irradiated conditions (‘oxygenated’). h) Cell viability assay treatmented by 3 with or without light. Kanai et al . [31] designed switchable photo-oxygenation catalysts ( 2 and 3 ) based on the Thioflavin T (ThT) structure, incorporating brominated benzothiazole and julolidine or a tetrahydroquinoline–peptide conjugate as key components (Figure 1e, 1f). Bromine substituents enhanced intersystem crossing (ISC) through heavy-atom effects, significantly increasing singlet oxygen (¹O₂) production upon light irradiation. The reduced HOMO-LUMO energy gap, attributed to the electron-accepting bromine and the electron-donating moieties, allowed longer wavelength absorption. These catalysts demonstrated effective oxidative degradation of Aβ aggregates, reducing their cytotoxicity under various conditions (Figure 1g, 1h). Similarly, Wang et al . [32] synthesized benzothiazole–naphthalene conjugates ( 4 and 5 ) that released ¹O₂ via their endoperoxide form (BZTN-O₂) to inhibit or reverse Aβ aggregation without requiring light activation, presenting a novel non-invasive therapeutic strategy (Figure 2a). In addition, a series of ThT derivatives 6-11 have been designed by Yan et al . [33] with electron-donating groups such as N, N-dimethylaminophenyl and triphenylamine, optimizing Aβ protein imaging and photo-oxidation (Figure 2b). 7 exhibited high singlet oxygen generation efficiency, effectively reducing Aβ aggregation and associated cytotoxicity. Meanwhile, Qu et al . [34] introduced a Cu ion-catalyzed in situ reaction for Aβ-targeted drug generation, forming compound 14 in situ imaging Aβ plaques (Figure 2c). This bifunctional drug extracted Cu from Aβ-Cu complexes, enabling photo-oxidation and mitigating Aβ-induced neurotoxicity in AD model organisms (Figure 2d). In 2024, Yan et al . [35] synthesized small molecules ( 15–18 ) to explore the impact of intramolecular freedom on photophysical processes (Figure 2e). 15 showed excellent Aβ plaque imaging and blood-brain barrier permeability, while 17 restricted intramolecular movement to enhance ¹O₂ generation, effectively inhibiting Aβ aggregation and reducing neurotoxicity (Figure 2f, 2g). However, the need for visible light ( λ = 500 nm) activation limits these strategies to in vitro applications, necessitating further exploration in AD animal models. Figure 2. a, b) Structure of photosensitizer 4-11 . c) Bifunctional compound 14 . d) Representative ThT-staining images of N2 and CL2006 in different treatment. e) Structure of photosensitizer 15-18 . f) ThT spectroscopy of photooxidation on Aβ42. g) The cell viability via 17 treatment with or without light. 3.1.2 Quinoline derivatives Small-molecule photosensitizers featuring donor-π-acceptor (D-π-A) structures have attracted significant interest. By incorporating flexible vinyl units into their π-conjugated backbones, these molecules enable rotational motion that facilitates non-radiative attenuation. This property enhances amyloid-β imaging by providing a strong fluorescence contrast. [36]. In 2022, Yan et al . [37] developed D-π-A photosensitizers ( 19–21 ) using a quinolinium scaffold as the acceptor, a dimethylaniline donor, and vinyl π-bridges of varying lengths (Figure 3a). Extending the ethylene bond length resulted in red-shifted excitation and emission wavelengths, reaching the near-infrared (NIR) region, which enhances deep tissue penetration, imaging, and photo-oxidation of Aβ [38,39]. Additionally, the N,N-dimethylamino moiety serves as an electron donor and specifically targets Aβ aggregates [40]. These structural modifications further shifted excitation and emission into the NIR region, improving imaging depth and Aβ photo-oxidation efficiency. Notably, 20 exhibited a 95-fold increase in fluorescence quantum yield upon binding to Aβ, inhibited Aβ aggregation via singlet oxygen generation, and reduced neurotoxicity through microglial lysosomal clearance under light exposure. Figure 3 . a) Structure of photosensitizer 19-21 ; Mechanism of photo-oxidation of Aβ by compound 20 . b) Chemical structure of photosensitizer 22-25 . c) Schematic diagram of selective photo-oxidation of Aβ40 aggregates by 24 . d) Structure of photosensitizer 26 and 27 . In 2024, Xiao et al . [41] designed quinolinium derivatives ( 22–24 ) targeting Aβ40 aggregates by optimizing steric hindrance of aromatic side chains with nitrogenous substituents. These catalysts exhibited superior selectivity for Aβ40 photo-oxidation, even at low inhibitor-to-protein ratios (I:P = 0.05), preventing toxic reassembly and reducing membrane binding (Figure 3b, 3c). Concurrently, Yan et al . [42] synthesized carbazole-based photosensitizers ( 26, 27 ) (Figure 3d) by shifting the donor-acceptor junction from the 2- to the 3-position of carbazole, resulting in a 4.3-fold increase in Aβ binding affinity and enhanced singlet oxygen generation. These advancements highlight the potential of D-π-A photosensitizers for Aβ imaging and photooxidative therapy. 3.1.3 Curcumin derivative To overcome the limited penetration depth of visible light, in 2009, Moore’ et al . designed a superior NIR Aβ fluorescent probe, 28 ( Figure 4a ) . and demonstrated its utility in in vivo imaging [43]. With an optimal emission wavelength (λmax(em) = 760 nm in methanol), compound 28 underwent in vitro testing. Upon entering the brain and binding to Aβ40, its fluorescence intensity increased by up to 70-fold, accompanied by a 90 nm blueshift and a substantial rise in quantum yield, exhibiting a distinct “turn-on” effect. Building on this work, Kanai’s group [44] synthesized a series of fluoroboron compounds as photoactivatable oxygenation catalysts targeting Aβ (Figure 4a). Similar to the above ThT derivative, the photocatalyst derivative 29 could identify the higher-order structures of pathogenic Aβ aggregates and generate singlet oxygen (¹O₂) to oxidize aberrant Aβ under 780 nm light irradiation. In summary, a bromine atom was introduced into the electron acceptor moiety of a fluorescent probe to enhance its oxygenation activity, while julolidine and tetrahydroquinoline were used to replace the two electron donor groups [44]. Additionally, a fluoro-pentafluoroethyl boron group, a stronger electron-withdrawing group than the previously used difluoroboron group, was incorporated into the electron acceptor moiety to improve the catalyst’s photostability. As a result, the tissue permeability of NIR light enabled photo-oxidation of aggregated Aβ beneath the skin of mice when irradiated from outside the body. Furthermore, when administered directly into the brain of an AD model mouse, 29 successfully oxygenated Aβ deposits in the affected areas, following NIR light irradiation using an LED-equipped optical fiber (Figure 4b, c). Figure 4 . a) Chemical structure of 28 and 29 . b-c) Photo-oxygenation Aβ in AD-model mouse by catalyst 29 . d) Chemical structure of 30 and ADLumin-4. e) Different modifications (red spheres) and cleavage site (red arrows) of Aβ40 by light. f) Chemiluminescence resonance energy transfer (CRET) diagram between ADLumin-4 and 30 . g) Immunoassay-measured concentrations of Aβ42. However, these studies have largely relied on external light sources, which have limited brain penetration, posing challenges for clinical application. In 2023, Ran et al . [45] demonstrate that ”molecular light” emitted by the chemiluminescent compound ADLumin-4 can effectively activate the photolabile curcumin-diazirine analogue 30 (Figure 4d), inducing structural modifications in Aβ peptides, the Methionine-35, Histidine-13 and 14 were oxidized and degraded, attenuating Aβ neurotoxicity (Figure 4e). Furthermore, they propose the use of chemiluminescent ADLumin-4 as a deliverable light source for in vivo therapeutic treatment, significantly reducing Aβ burdens in 5xFAD mice when combined with 30 . The study also employs molecular imaging using the ADLumin-1 probe to monitor phototherapy efficiency under both LED light and ADLumin-4 treatment, highlighting the potential of ”molecular light” in photodynamic therapy and its application in mitigating Aβ neurotoxicity (Figure 4f,g). 3.1.4 Boron-dipyrromethene (BODIPY) BODIPY, a widely used fluorescent dye, is characterized by low dark toxicity, high extinction coefficients, and minimal photobleaching quantum yields. The addition of heavy halogen atoms into the pyrrole ring enhances triplet state yield, thereby improving its performance as a photosensitizer in PDT due to the increased intersystem crossing (ISC) efficiency under photoirradiation [46,47]. Additionally, BODIPY conjugated with an electron donor through a π-conjugation system serves as an effective motif for amyloid-sensing fluorescent probes. [48-50]. Building on these properties, Takanobu’s group [51] designed an iodinated BODIPY-based photo-oxygenation catalyst targeting Tau protein, which effectively reduced Tau propagation by inhibiting its seeding activity (Figure 5a). The new photocatalyst, designated as 31 , was developed through several structural modifications to the BODIPY core. First, an iodine atom was incorporated at the C2 position of the BODIPY framework to enhance intersystem crossing (ISC). Additionally, a 1,2,3,4-tetrahydroquinoline group with strong electron-donating characteristics was introduced, narrowing the energy gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) (Figure 5a). Using the same molecule, in 2021, Tomita et al . [52] successfully used 31 for photo-oxidation of Aβ aggregates in AD model mice (Figure 5b). The results show that upon irradiation at 660 nm, photo-oxidation catalyzed by 31 was demonstrated with aggregated Aβ deposited in the brains of sporadic AD patients. Besides the oxygenated products, a 10 kDa Aβ derivative, likely a dimer formed via cross-linking at the oxygenated His residues, was observed in the catalytic photo-oxidation reaction using 31 in the brain of 7-month-old App NL-G-F/NL-G-F mice. Metabolism analysis revealed that microglia were responsible for the rapid clearance of oxygenated Aβ aggregates, and photo-oxidation facilitated Aβ degradation via the endo-lysosomal pathway. While the precise mechanism of artificial photo-oxidation in amyloid degradation remains unclear, these findings provide valuable insights into the photodynamic clearance of Aβ in vivo (Figure 5c). Figure 5 . a) Chemical structure of BAP-1 and 31 . b) Schematic illustration of photo-oxygenation in App NL-G-F/NL-G-F mice. c) Western blot results of Aβ for the hippocampi in mice; cat. = photo-catalyst injection. 3.1.5 N or O heterocyclic compounds N- or O- heterocyclic compounds, including riboflavin (vitamin B2), rose bengal (RB), methylene blue (MB), and other photosensitizers, have been extensively investigated for their applications in antibacterial and AD therapy. These compounds are known for their high triplet quantum yields and low phototoxicity, making them promising candidates for therapeutic use. [9]. Additionally, their low cytotoxicity under dark conditions makes them suitable for biomedical uses, while strong absorption in the visible to near-infrared range allows deeper tissue penetration for activation at clinically relevant wavelengths [53,54]. Additionally, their molecular framework allows for structural modifications, enhancing photophysical properties and selectivity toward biological targets like tumor or bacterial cells. Collectively, these features highlight nitrogen-oxygen heterocyclic photosensitizers as promising agents for neurodegeneration therapeutic. In 2008, Nakayama et al . [55] identified 1,2,4-oxadiazole derivatives ( 32 ) was identified as a probe for Aβ plaques (Figure 6a), which were later modified by Mangione et al . to inhibit Aβ aggregation via UV-light-induced cross-linking, leveraging a mechanism similar to photo-induced cross-linking of unmodified proteins (PICUP) [56,57]. The authors attributed the inhibitory effect of the oxadiazolic compound to the generation of reactive intermediates that interact with the amino acid backbone of Aβ40. These intermediates extract an electron from the tyrosine residue of Aβ40, creating a reactive form of Aβ40. The reactive Aβ40 peptides then cross-link with neighboring Aβ40 monomers, forming dimers and preventing further aggregation. Addressing the limitations of UV activation, Zhang et al . [58] developed rofecoxib-based NIR photosensitizers ( 33-35 ) with enhanced imaging and therapeutic efficacy through selective binding and photo-oxidation of Aβ aggregates, achieving deep-tissue imaging and degradation (Figure 6b, c). Concurrently, riboflavin (vitamin B2, 36 ) was explored by Kanai et al . [59] as a visible-light-activated catalyst for Aβ photo-oxidation, disrupting amyloid fibrils and reducing Aβ aggregation and neurotoxicity [60]. Derivatives of riboflavin ( 37 ) further enhanced specificity and therapeutic potential, particularly when combined with oxygenated antibodies (Figure 6d-g). Figure 6. a,b) Chemical structures of 32-35 . c) Fluorescence spectra and fluorescence intensity of photosensitizers after coincubation with Aβ aggregates in PBS. d) Structures of vitamin B2 ( 36) and its derivative 37 . e) MALDI-TOF mass spectra of Aβ after light stimulation. f,g) ThT fluorescence assay and cell viability after light. Rose bengal ( RB, 38 ) and methylene blue ( MB ) have also demonstrated utility in light-assisted AD treatment. Park et al . [61] identified RB as a potent green-light-activated photosensitizer that modulates Aβ42 aggregation, preventing β-sheet formation and reducing cytotoxicity (Figure 7a-d). Additionally, RB has shown potential as a sonooxygenation catalyst for AD therapy [62]. MB, with its ability to cross the blood-brain barrier, has been extensively studied for AD [63,64], initially showing efficacy in inhibiting toxic Aβ oligomer formation [65] and alleviating behavioral impairments in mouse models. Although a Phase III trial failed to demonstrate clinical benefit [66], subsequent studies highlighted MB’s enhanced therapeutic effects under visible light, particularly in photo-oxidation of Aβ42 residues [67], where illumination restored locomotion in an AD Drosophila model (Figure 7e). These findings underscore the importance of light-assisted strategies in optimizing the therapeutic efficacy of small-molecule photosensitizers for AD. Figure 7. a) Structure of RB, 38 . b) Schematic illustration of photo-excited RB suppressing Aβ aggregation. c) CD spectra (inset: images of red, green, and blue LEDs). d) AFM images of Aβ42 solutions treated with RB under LED illumination. e) Schematic diagram of MB , 39 against AD in vivo and in vitro. 3.1.6 Porphyrins and its derivatives Since its introduction in the 1960s, porphyrins have been widely applied due to their high singlet oxygen yields and Q-band energy levels [68,69]. Toshima et al . [70] demonstrated that porphyrin derivatives ( 40 and 41 ) inhibit Aβ42 aggregation more effectively under photoirradiation, with compound 41 also disrupting Aβ oligomers and significantly mitigating Aβ42-induced cytotoxicity in PC12 cells (Figure 8a, b). Park et al . [71] advanced this work with meso–tetra(4-sulfonatophenyl)porphyrins (TPPS, 42 ), showing that metal center variations in the porphyrin ring modulate anti-aggregation effects and Aβ toxicity under blue light. In a Drosophila model, TPPS alleviated Aβ-induced neurodegenerative symptoms, indicating potential as a phototherapeutic agent (Figure 8c, d). Figure 8. a) Structure of porphyrin derivatives 40 and 41 . b) ThT spectra of Aβ42 fibrils with (red line) and without (blue line) photo-irradiation by 40 and 41 . c) Structure of 42 and photo-oxidation mechanism. d) Schematic diagram of the operation of photocatalyst 42 in Drosophila , 42 is mixed with Drosophila food (right). e) The structure of T-ZnPc, 43 and mechanism of photodegradation of Aβ. f) Structure of Ce6, 44 . g) TEM images of Aβ treatment by 44 . h, i) ThT spectra of Aβ effected by 44 and cell viability by Cu 2+ treatment. Building on these advancements, thymine-modified Zn phthalocyanine (T-ZnPc, 43 ) was designed to target Fe³⁺ and Al³⁺ ions, commonly enriched around Aβ protofibrils [72]. This compound demonstrated enhanced PDT activity, producing abundant ROS to degrade Aβ protofibrils and reduce neurotoxicity, as validated through spectroscopic and cytometric analyses (Figure 8e). Chlorin e6 ( Ce6, 44 ), a chlorin derivative with favorable stability, low dark toxicity, and high singlet oxygen quantum yield [73,74], was found by Rahimipour et al . [75] to selectively bind Aβ40 and inhibit aggregation. Ce6 photoexcitation catalyzed histidine-targeted damage at Aβ residues H6, H13, and H14, inducing cross-linking and chelating Cu²⁺ to inhibit Cu²⁺-induced aggregation (Figure 8f-i). These findings underscore the versatility of porphyrin-based and chlorin-based photosensitizers for Aβ-specific photodynamic therapy, providing innovative therapeutic options for AD. 3.1.7 Fullerene and its derivatives Fullerenes, discovered in 1985 [76], are the third major carbon allotrope after diamond and graphite, possessing unique properties such as high electron affinity, a large surface-to-volume ratio, and efficient singlet oxygen (¹O₂) generation under UV light. These features have made fullerene derivatives promising photosensitizers in PDT [77,78]. In 2010, Toshima et al . first demonstrated their potential in targeting Aβ aggregation, designing 43 and 44 , where the fullerene moiety exhibited high affinity for the KLVFF sequence of Aβ42 (Figure 9a) [79]. 43 inhibited Aβ42 aggregation in a concentration-dependent manner, with enhanced efficacy under UV irradiation, as confirmed by TEM and EPR analyses (Figure 9b). The photoinduced degradation was attributed to ROS generated by photoexcited fullerenes, effectively preventing the formation of high-molecular-weight Aβ42 aggregates. Figure 9. a) Structures of fullerene derivative 43 and 44 . b) TEM image of Aβ42 fibril before and after illumination by 43 . c) Structures of fullerene derivative 45 and 46 . d) ThT spectra of Aβ42 fibrils with (red line) and without (blue line) photoirradiation by 45 . e, f) UCNP@C60-pep inhibited Aβ aggregation, attenuated oxidative stress to prolong the lifespan of the CL2006 elegans. To improve solubility, Toshima et al . [80] introduced water-soluble groups into fullerenes, creating 45 and 46 (Figure 9c). These derivatives also degraded Aβ under light and reduced Aβ-induced cytotoxicity in PC12 cells. Specifically, 45 significantly improved cell survival rates under light conditions, establishing fullerene-sugar hybrids as potential anti-Aβ agents(Figure 9d). However, the shorter emission wavelength of fullerenes limits in vivo applications. To address this, Du and co-works [81] developed UCNP@C60-pep, a theranostic platform combining C60 with an Aβ-targeting peptide on upconversion nanoparticles (UCNP) (Figure 9e). Under NIR light, UCNP@C60-pep produced ROS to oxidize Aβ aggregates by covalently modifying hydrophobic clusters with hydrophilic oxygen atoms, thereby disrupting aggregate formation and offering a synergistic approach for AD treatment (Figure 9f). 3.1.8 Azobenzene–boron complex Fused azobenzene–boron complexes (BAz), first synthesized by Hohaus and Wessendorf in the 1980s, exhibit strong near-infrared (NIR) emission and electron-accepting properties due to the electron deficiency of the nitrogen–nitrogen double bond (N=N) and boron–nitrogen (B–N) coordination. These features significantly lower the LUMO energy of the azobenzene ligand, enabling aggregation-induced emission (AIE) in dilute solutions. A donor–acceptor (D–A) copolymer of bithiophene (BT) and BAz demonstrates photoluminescence (PL) in the NIR region (λPL = 751 nm, ΦPL = 0.25), making BAz a promising photoluminescent compound [82]. Inspired by BAz structures, Kanai et al . [27] synthesized a series of catalysts for photo-oxidation applications, starting with catalyst 47 (Figure 10a). Structural modifications, including the incorporation of ”heavy atom” effects, led to catalyst 48 , which exhibited enhanced intersystem crossing (ISC) and singlet oxygen (¹O₂) generation. Further modifications with CF₃ groups and amino moieties yielded catalysts 49 and 50 , which displayed superior water solubility (>100 μM in phosphate buffer) and absorption in the orange light region (λ = 578 nm), facilitating deeper tissue penetration (Figure 10b). Catalyst 50 successfully oxygenated Aβ in living mice via peripheral administration (Figure 10c). However, its efficacy was limited due to moderate activity, lack of performance in AD patient brain lysates, and side effects such as scalp injury caused by low BBB permeability and insufficient target selectivity. To address these challenges, a prodrug strategy was developed [83,84], resulting in catalyst 51 , which converts into catalytically active 52 upon photoirradiation near Aβ aggregates via an autocatalytic hydrogen atom transfer (HAT) mechanism (Figure 10d). This approach significantly improved activity-by two orders of magnitude over catalyst 50 -and allowed for selective, non-invasive photo-oxidation of Aβ in AD model mice without scalp injury [85]. Catalyst 51 also demonstrated high BBB permeability and amyloid selectivity, successfully oxygenating Aβ and tau amyloids derived from AD patients. These results highlight its potential as a multi-targeting agent for AD treatment. Figure 10. a) BBB-permeable photo-catalyst 47 enables the selective and direct degradation of extracellular Aβ proteins. b) Molecular design of photooxygenation catalyst 48-50 . c) Schematic diagram of 50 in vivo therapy. d) Catalytic photooxygenation of amyloids using a prodrug strategy; photooxygenation of Aβ proteins mediated by leuco ethyl violet 51 as a pro-catalyst. 3.1.9 Transition metal complexes Transition metal complexes have gained considerable attention for their tunable geometries, robust structural stability, and long-lived photoexcited states, making them attractive candidates for applications ranging from energy conversion and catalysis to drug delivery and cancer therapy [86–90]. Recently, their potential has been explored in the context of photo-degradation of Aβ in AD. In 2016, Aliyan et al . [91] introduced a rhenium (I) complex, [Re(CO)₃(dppz)(Py)]⁺ ( 53 ), which displayed UV-light-induced oxidation of Aβ aggregates. Upon binding to Aβ fibrils, the complex exhibited an 18-fold enhancement in photoluminescence (K d = 4.2 ± 0.6 µM) [92] in phosphate buffer, followed by a remarkable 105-fold increase upon prolonged UV exposure, attributed to the oxidation of Aβ residues near the binding sites of the complex. LC-MS analysis revealed a 16 m/z mass shift in irradiated Aβ samples, confirming the incorporation of oxygen into the peptide. Photochemical ”footprinting” identified Val18 and Phe20 as key binding residues (Figure 11a). This approach underscores the therapeutic potential of photo-oxidative strategies for inhibiting Aβ aggregation and mitigating its toxicity. Figure 11. a) Re (I)-based complex 53 facilitates light-driven oxidation of Aβ fibrils while simultaneously identifying molecular binding sites on the surface of Aβ fibrillar aggregates. b) Mechanistic depiction of Ru(II)-based complex 54 as a sensitive and biocompatible anti-Aβ agent, enabling visible light-triggered dissociation of β-sheet-rich Aβ aggregates. c) Chemical structures of Ru (II)-based complex 55-57 . d) Ir(III)-based complex 58 oxidation of Aβ is promoted by light-activated. e,f) Ir(III)-based complex 59 employs a coordination-/photo-mediated oxidation strategy to modify amyloidogenic peptides. g) Chemical structures of Ru-BODIPY complex 60 and Ir-BODIPY complex 61 . Ru(II) complexes, such as [Ru(bpy)₃]²⁺ ( 54 ), have emerged as promising alternatives for light-mediated treatment of Aβ aggregates due to their visible-light activity, biostability, and long-lived photoexcited states (τ = 1 µs) [93]. Under white LED illumination, [Ru(bpy)₃]²⁺ generated singlet oxygen (¹O₂), disassembling β-sheet amyloid structures and reducing Aβ fibril size from 818.2 nm to 137.6 nm, significantly mitigating Aβ-induced neurotoxicity in vitro (Figure 11b). Ru(II) complexes also demonstrated binding affinity to Aβ peptides, reduced toxicity, and acted as fluorescent probes for amyloid fibrils and oligomers [94–96]. Other Ru(II) polypyridyl complexes have been found to inhibit Aβ aggregation, reduce acetylcholinesterase (AChE) activity, and offer protection against ROS. [97,98]. Bataglioli et al . [99] reported photoactivable Ru(II) complexes ( 55–57 ), which promoted covalent binding to His residues on Aβ peptides, inhibiting oligomer formation and enhancing their therapeutic potential (Figure 11c). Ir(III) complexes have gained attention as alternative photooxidants for amyloid peptides, offering potential advantages over Ru(II) complexes that require electron acceptors like ammonium persulfate to induce oxidation, which can cause undesirable toxicity in cells [100-102]. Kang et a l. [103] developed an Ir(III) complex ( 58 ), designed for efficient ¹O₂ generation (ΦΔ = 0.25) under mild conditions, which selectively oxidized Met35, His13/14, and Tyr residues in amyloidogenic peptides, including Aβ, α-Syn, and hIAPP (Figure 11d). The oxidation of these sites disrupted aggregation pathways, providing a basis for selective amyloid modulation. Building on this, a ”two-pronged” strategy combining covalent coordination and photo-oxidation was proposed. For example, complex 59 [104], incorporating fluorine atoms for hydrogen bonding, covalently bound to Aβ species and degraded aggregates upon sunlight exposure, significantly reducing cytotoxicity in Neuro-2a cells (Figure 11e, f). Recent studies explored boron-dipyrromethene (BODIPY)-based metal complexes [105], such as Ru-BDP ( 59 ) and Ir-BDP ( 60 ), for Aβ peptide oxidation and aggregation modulation. These photosensitizers efficiently generated ROS upon activation, altering Aβ aggregation pathways and morphologies, with complex 60 exhibiting the highest efficiency in reducing Aβ toxicity (Figure 11g). These advancements highlight the therapeutic potential of transition metal complexes for targeted amyloid modulation, emphasizing their utility in developing innovative strategies for AD treatment. 3.2 Metal nanoparticles Gold nanoparticles (AuNPs) have become a versatile platform for catalysis, drug delivery, and disease diagnosis/treatment, owing to their biocompatibility, unique optical properties, and ease of functionalization [106,107]. In AD-related studies, AuNPs and gold nanoclusters (AuNCs) have been employed to modulate Aβ fibrillation in both intracellular and extracellular spaces [108]. Notably, AuNCs encapsulated in human serum albumin (HSA) proteins exhibit photo-oxygenation capabilities. Upon NIR light exposure, AuNCs@HSA-B generates singlet oxygen (¹O₂), effectively oxidizing Aβ monomers without significant adverse effects on surrounding cells, leveraging HSA’s specific binding to Aβ (Figure 12 a-d) [109]. Additionally, Ge’s group. [110] designed dumbbell-shaped Au-CeO₂ nanocomposites by coating gold nanorods with CeO₂ nanoparticles. These constructs demonstrated photocatalysis and photothermal effects under NIR irradiation, with further enhancement through Aβ-targeted peptide (KLVFF) modifications. The resulting Aβ-targeted nanocomposite (K-CAC) improved cognitive function in AD mice, though long-term in vivo toxicity studies are needed to validate clinical applicability (Figure 12e). Figure 12. a) The synthesis process for AuNCs@HSA and AuNCs@HSA-B. b) Illustration of Aβ aggregation inhibition via photo-oxygenation. c) Normalized final ThT fluorescence intensities indicating the extent of Aβ aggregation. d) Time-dependent changes in ThT fluorescence demonstrating Aβ aggregation dynamics. e) Multimodal therapy for AD utilizing Au NRs combined with semiconductor CeO2, which leverages antioxidant stress, photocatalysis, and photothermal effects to target and inhibit Aβ. Metal–organic frameworks (MOFs), consisting of metal cations or clusters linked by organic ligands, possess intrinsic porosity and chemical versatility, making them valuable in drug delivery, bioimaging, and catalysis [111,112]. Among them, porphyrinic MOFs (PMOFs) are particularly promising photosensitizers for inhibiting Aβ aggregation. PMOFs leverage four mechanisms: i) preventing self-quenching: periodic porphyrin ligand arrangements ensure efficient photoactivation [113]; ii) enhanced oxygen accessibility: porous structures promote ¹O₂ generation; iii) specific Aβ interactions: exposed metal sites and aromatic porphyrin rings enhance Aβ binding, minimizing off-target effects; iv) copper chelation: mitigates copper-induced neurotoxicity [114,115]. Figure 13. a) Construction of PCN-224 nanoparticles and mechanism of photo-inhibition of Aβ42 aggregation. b) Proposed mechanism illustrating how POMFs suppress amyloid fibril formation. c) Construction of Ru 3+ -NMOFs nanozymes and disruption of Aβ aggregation in the C.elegans model. d) Synthesis of penicillamine-modified FexCuySe nanoparticles. e) Schema of AD mice model under administration of D-NPs. f) Levels of Aβ42 in CSF measured after a 60-day of combined D-NPs and NIR light treatment period. For example, Wang et al . [116] synthesized Zr-based PMOF nanoparticles (PCN-224), which demonstrated stable frameworks, efficient ¹O₂ generation, and strong Cu(II) chelation. These properties significantly reduced Aβ42 aggregation and cytotoxicity under NIR irradiation (Figure 13a, ). Yu et a l. [117] extended this work by functionalizing Hf-based PMOFs with Aβ-targeting peptides (LPFFD), enhancing selectivity and oxidation efficiency. These constructs alleviated Aβ-induced paralysis in C. elegans, showcasing in vivo therapeutic potential (Figure 13b). Yang et al . [118] introduced a combinational platform, PCN−222@ICG@RVG, which combines photothermal and photo-oxygenation therapy for enhanced Aβ aggregation inhibition. Additionally, Xu et al . [119] developed Ru³⁺-chelated nanoscale MOFs (Ru³⁺-NMOFs) that inhibited Aβ aggregation and reduced associated inflammation (Figure 13c). These constructs successfully alleviated Aβ plaques and symptoms of paralysis in C. el[egans models. The interplay of PDT and chirality presents innovative pathways to modulate Aβ aggregation. Natural Aβ forms left-handed helical fibrils, making chirality a critical design factor [120,121]. Zhang and co-works [122] fabricated chiral L/D-FexCuySe nanoparticles, which oxidized Aβ42 monomers and disassembled mature fibrils under NIR-light irradiation (808 nm). D-FexCuySe nanoparticles exhibited superior binding affinity and ROS generation compared to their L-counterparts, effectively reducing Aβ42 concentrations in transgenic mouse models (Figure 13d-f). Polyoxometalates (POMs), inorganic molecules with photocatalytic properties, have also shown promise in Aβ aggregation modulation. For instance, K₈[P₂CoW₁₇O₆₁], a phosphotungstate with a Wells–Dawson structure, inhibited Aβ self-assembly via UV-light activation [123,124]. However, UV irradiation’s potential harm limits its clinical translation. These studies underscore the potential of AuNPs, MOFs, chiral nanoparticles, and POMs in AD therapy. However, further investigations into long-term safety, targeted delivery, and clinical translation are imperative to realize their therapeutic potential. 3.3 Carbon Dots nanomaterials Carbon dots (CDs) have gained attention as promising nanomaterials for modulating Aβ aggregation due to their low cost, water solubility, biocompatibility, and tunable fluorescence. Branched polyethylenimine-coated CDs (bPEI@CDs) effectively inhibit Aβ aggregation and dissociate preformed fibrils via electrostatic interactions. Under light activation, bPEI@CDs generate reactive oxygen species (¹O₂), significantly enhancing their efficacy and increasing PC12 cell viability from 55% (untreated) to 79% (Figure 14a) [125]. To enhance in vivo Aβ clearance, Yan et al . [126] developed yellow fluorescent carbon dots (yCDs-Ce6) with photothermal properties, capable of inhibiting and eliminating Aβ42 in deep brain regions under 808 nm laser irradiation. Additionally, yCDs-Ce6 demonstrated antimicrobial activity through combined photodynamic and photothermal effects (Figure 14b). Figure 14. a) Synthesis of penicillamine-modified FexCuySe nanoparticles. b) Schema depicting the construction of yCDs and yCDs-Ce6 and exploiting the synergistic effect of PTT and PDT to inhibit Aβ aggregation and microbial infection. c) ERCD ameliorates several symptoms of AD by photo-oxidizing Aβ. d) Improved survival of wild-type (N2) or AD (CL2006) elegans after co-incubation with ERCD-1 under NIR illumination and survival of nematodes under a concentration gradient of ERCD-1 and NIR light. Photosensitizer-doped carbonized polymer dots (PS-CPDs), synthesized by Sun’s group [127] via a hydrothermal method, generate ¹O₂ under near-infrared (NIR) light and effectively inhibit Aβ fibrillization at low concentrations. These PS-CPDs also disaggregate Aβ fibrils, reduce amyloid plaque deposition, and alleviate Aβ-induced cytotoxicity, extending the lifespan of AD nematodes (Figure 14c). Dual-carbon dot nanomotors (ERCD) [128], combining near-infrared carbon dots (RCD) and epigallocatechin gallate-derived polymer dots (ECD), further enhanced these properties. Under NIR irradiation, ERCD inhibited 92% of Aβ40 fibrillization, disassembled fibrils, reduced cytotoxicity, and prolonged nematode lifespan by 6 days. ERCD’s multifunctionality stems from its ability to generate ROS, which efficiently oxidizes amino acid residues in Aβ (Figure 14d). These studies highlight the potential of CDs as nanotherapeutics for AD. Future research should focus on optimizing targeting, improving in vivo stability, and advancing clinical translation to maximize their therapeutic efficacy. 3.4 Polymeric nanoparticles Polymeric nanoparticles (PNPs) stand out in medical applications for their biodegradability and biocompatibility [129,130]. Tailored’s group designed, such as hydrophobic group-modified polyamidoamine dendrimers (PAMP) [131], curcumin-conjugated poly(carboxybetaine methacrylate) (Cur@pCB) [132], and mixed-shell polymeric micelles (MSPM) [133], show potential in Aβ inhibition. Zhang et al . [134] designed a PDT micelle system with tanshinone I (TAS) and chlorine6 (Ce6), using a PEG-b-PDPA diblock copolymer. This system efficiently degraded Aβ protofibrils and suppressed fibrillation upon NIR irradiation (Figure 15a). Qu et al . [135] developed PKNPs, composed of porphyrin derivatives and Aβ-targeting peptides, which selectively oxidized Aβ under visible light, reducing Aβ plaques and extending the lifespan of C. elegans CL2006 (Figure 15b, c). Figure 15. a) Construction of TAS-loaded photodynamic micelle and utilizing the photodynamic effect of Ce6 to degradation Aβ aggregates and inhibition of Aβ fibrillation. b) ROS-activated PKNPs trigger Aβ disassembly. c) The representative images of Aβ deposits stained by ThS in the C. elegans. White arrows point to Aβ plaques. d,e) Construction of T-LD NPs, along with a schematic showing fluorescence imaging of Aβ and ROS generation under laser irradiation to inhibit Aβ aggregation and disaggregate Aβ fibrils. f) Schematic diagram of the synthesis of BD-Se-QM/NPs and the in Situ Chemical Excitation of BD-Se-QM/NPs by H2O2 to Oxidize Aβ1-42 Aggregates, Promoting Uptake by Microglial Cells (BV2). g) TEM images of Aβ1–42 aggregates incubated with BD-Se-QM/NPs under different conditions. Aggregation-induced emission luminogens (AIEgens) excel as imaging and PDT agents due to bright fluorescence and ROS generation [136-140]. Dong et al . [141] created T-LD NPs by combining AIEgen TPMD with DSPE-PEG-CLPFFD, an Aβ-binding polymer. These NPs effectively suppressed fibrillization, disrupted fibrils, and reduced Aβ neurotoxicity from 36% to 10% (20 μg/mL), while decreasing Aβ deposits and extending the lifespan of C. elegans (Figure 15d,e). Chi et al . [142-145] introduced oligo-p-phenylene ethynylene compounds (OPEs) that selectively bind Aβ fibrils and generate singlet oxygen upon illumination, oxidizing fibrils into shorter, nontoxic structures. OPE12⁻ showed selective oxidation compared to methylene blue, highlighting its potential in targeted PDT [146]. Chemiluminescence (CL) offers energy-free activation for PDT with high specificity [147-149]. Yan et al . [150] developed a nanocomposite with a photosensitizer ( BD-6-3 ) and CPPO in mesoporous silica nanoparticles (MSNs). Upon reacting with H₂O₂, the system generated singlet oxygen, reducing Aβ neurotoxicity and enhancing cell viability. To improve blood-brain barrier penetration, Yan et al . [151] introduced a G-poly(oxalate)-based nanosystem encapsulating BD-Se-QM and CPPO. This system inhibited Aβ42 aggregation and reduced neurotoxicity through controlled H₂O₂-responsive drug release, offering a precise therapeutic approach (Figure 15f, g). Polymeric nanoparticles, AIEgen-based photo-oxidants, and chemiluminescence strategies demonstrate promising therapeutic potential for AD. Further optimization in targeting, in vivo stability, and clinical translation will be crucial for advancing these strategies toward practical applications. 3.5 Upconversion nanoparticles (UCNPs) Photo-oxidation strategies have shown potential for inhibiting Aβ aggregation, but the reliance on UV or visible light for photosensitizer activation poses challenges, including limited tissue penetration and UV-induced damage. Lanthanide-doped up-conversion nanoparticles (UCNPs), with their NIR light excitation, large anti-Stokes shift, and high stability, have emerged as promising tools to overcome these limitations [152,153]. UCNPs effectively convert NIR light into UV or visible light, enabling applications in PDT and expanding their utility in AD treatment. Kuk and co-workers [154,155] introduced a UCNP-based platform using a NaYF4/Er core and a rattle-structured organosilica shell with photosensitizers, such as Rose Bengal (RB). Under NIR excitation, the system generated singlet oxygen (¹O₂), effectively inhibiting Aβ42 aggregation and mitigating associated cytotoxicity (Figure 16a). However, limited Aβ selectivity hindered its in viv o applicability. Addressing this, Du et a l. [81] developed UCNP@C60-pep by conjugating an Aβ-targeting peptide (KLVFF) and fullerene C60 onto the UCNP surface. This platform utilized C60’s dual ROS-regulating capabilities, generating ROS for Aβ photo-oxidation under light and quenching excessive ROS to maintain redox balance in darkness. UCNP@C60-pep suppressed Aβ aggregation and alleviated paralysis in C. elegans CL2006 (Figure 9f). Figure 16. a) Mechanism of generation of 1 O 2 in the Rattle-structured UCNPs by irradiating the UCNP core and transferring energy to the loaded RB. b) Diagram of UCNPs@SiO2-ThS nanoparticle synthesis and preventing Aβ42 monomer aggregation and brealing down Aβ42 fibrils by UCNPs@SiO2-ThS nanoparticles. c) Constrcution of UCN/Cur@EM and utilized as PDT agent for suppressing Aβ aggregates. To enhance selectivity and reduce side effects, UCNPs@SiO2-ThS [156], incorporating thioflavin-S, were developed for localized photo-oxidation. These nanoparticles inhibited Aβ42 monomer aggregation and disassembled fibrils through their photooxidative capacity (Figure 16b). More recently, biomimetic UCNP/Cur@EM nanoparticles, modified with erythrocyte membranes and loaded with curcumin, were shown to recruit Aβ aggregates and confine photosensitizers in proximity for efficient ROS generation [157]. Under NIR irradiation, this system reduced Aβ-induced neurotoxicity in vitro and in vivo (Figure 16c). UCNP-based platforms effectively overcome the limitations of traditional photo-oxidation strategies in Aβ modulation, offering selective and efficient approaches for AD treatment. Further innovations in UCNP design and functionalization hold promise for advancing AD therapy. 3.6 Two-Dimensional Nanomaterials Two-dimensional (2D) nanomaterials such as black phosphorus ( BP ), carbon nitride ( C3N4 ), and graphene oxide ( GO ) have emerged as promising candidates for PDT in AD treatment due to their efficient photoinduced electron-hole separation for ROS generation. These materials possess atomic-layered structures and offer advantages such as simple preparation, functionalization, programmable energy bandgaps, large specific surface areas, and adjustable optical properties, making them highly versatile in biomedical applications [158-160]. BP, a metal-free layered semiconductor, has garnered significant attention for its unique electrical, optical, and thermal properties, as well as its biocompatibility and biodegradability [161]. Notably, BP nanosheets can cross the BBB through photothermal transition under NIR laser irradiation [162]. Qu et al . [163] developed BP nanosheets functionalized with 4-(6-Methyl-1,3-benzothiazol-2-yl) phenylamine (BTA), forming BP@BTA through C-P covalent bonds. This functionalization not only enhances affinity for Aβ peptides but also slows BP degradation, allowing continuous singlet oxygen (¹O₂) production under NIR irradiation. The BP@BTA system reduced Aβ-induced toxicity and extended the lifespan of C. elegan CL2006 (Figure 17a, b). However, repeated BP nanosheet injections were found to induce liver and renal toxicity in viv o [164], necessitating the development of less toxic 2D nanomaterials. Silicene nanosheets (SNSs) have shown significant promise in disassembling Aβ33-42 fibrils into shorter fibrils, rod-like structures, or nanofilms under NIR irradiation, achieving a degradation rate of up to 96.47% for β-sheet secondary structures [165]. These findings highlight the potential of SNSs as safer alternatives to BP in PDT applications. Figure 17. a) Diagram of BP@BTA generating 1 O 2 under NIR to suppress Aβ aggregation. b) BP@BTA extended the lifespan and mitigated Aβ-induced toxicity in CL2006 nematodes. Fluorescence imaging of Aβ deposits in C.elegan after BP@BTA (25 µg/mL) administration and NIR irradiation. c) Illustration of g-C3N4 nanosheets as inhibitors of Aβ aggregation. Upon exposure to visible light, g-C3N4 generates ROS through interactions with oxygen molecules, leading to disrupted fibril formation. d) Schema of g-C3N4@Pt nanosheets as photodynamic agent and designed for AD therapy. g-C3N4, a 2D ultrathin nanomaterial composed of carbon and nitrogen, offers a high surface-to-volume ratio, tunable electronic structure, excellent biocompatibility, and favorable fluorescence properties [166-168]. In 2016, Chung et al . [169] demonstrated that g-C3N4 nanosheets produce ROS, including ¹O₂ and superoxide radicals (•O₂⁻), under visible light, effectively preventing Aβ aggregation and inducing photo-oxidation (Figure 17c). Among various derivatives, Fe-doped g-C3N4 (Fe@CN) displayed enhanced ROS generation and anti-aggregation efficiency, achieving a 91% cell viability in PC12 cells treated with Aβ under white LED illumination compared to 55% in untreated controls. Building on this, Qu et al . [170] developed a platinum-functionalized g-C3N4 (g-C3N4@Pt) (Figure 17d), where Pt²⁺ ions improved electrostatic interactions with Aβ peptides, significantly increasing cell viability to 92% under visible light. The integration of gold nanoparticles (AuNPs) further enhanced charge separation and ROS generation, facilitating Aβ disassembly through production of H₂O₂, •O₂⁻, and HO• radicals [171]. Graphene-based materials, such as graphene oxide (GO) and reduced graphene oxide (rGO), are flexible 2D carbon nanosheets with abundant functional groups (e.g., carboxyl and hydroxyl groups), photothermal properties, and biocompatibility [172]. In addition to inhibiting Aβ aggregation, efforts have been directed towards disassembling mature fibrils. A GO-modified g-C3N4 composite (GO/g-C3N4) demonstrated effective disassembly of fibrils under UV-light irradiation via H₂O₂-mediated ROS production [173]. The advancements in 2D nanomaterials, including BP, g-C3N4, and GO, underscore their therapeutic potential in mitigating Aβ pathology in AD. Continued research into reducing toxicity and enhancing functionalization will further expand their applicability in PDT-based strategies for AD treatment. Photothermal therapy In AD therapy, PTT leverages the photothermal effect of photothermal transduction agents (PTAs) to harvest energy from light and convert it into heat, raising the surrounding temperature and triggering changes in Aβ aggregation. The key criteria for an ideal PTA include excellent light harvesting ability in the NIR region, high photothermal conversion efficiency (PCE), good photothermal stability, and biosafety. Similar to PDT, PTT is a non-invasive treatment that allows precise targeting of affected areas through controlled light irradiation, minimizing systemic side effects and reducing damage to surrounding healthy tissues [174]. However, PTT for AD therapy faces three main challenges: (1) limited light penetration depth, (2) drug delivery across the blood-brain barrier, and (3) achieving an optimal photothermal temperature. Beyond penetrating the skin, the light must also pass through the skull to reach brain tissues, which is a critical requirement for its application. NIR light is the most suitable light source for PTT due to its higher photon energy, lower tissue absorption and scattering, and deeper penetration compared to ultraviolet or visible light [175]. Therefore, developing NIR-responsive photothermal agents is a key solution. On the other hand, photothermal therapy should focus on low-temperature PTT, as non-specific heating and thermal diffusion from strong laser irradiation can damage nearby healthy tissues [176]. A key challenge in treating neurodegenerative disorders is the BBB, which restricts systemic drug delivery to the central nervous system (CNS). Advances in nanotechnology offer new strategies, such as photothermal and ultrasound techniques, to enhance BBB permeability for effective therapeutic delivery. Increased physiological temperature can elevate BBB permeability by downregulating VE-cadherin and loosening tight junctions between endothelial cells. Overall, the photothermal effect facilitates more effective drug delivery across the blood-brain barrier into the brain, giving PTT a natural advantage in the treatment of AD. Currently, PTT-based AD treatments primarily focus on disrupting amyloid-beta aggregation using the photothermal effect, as amyloid aggregation is highly sensitive to heat. Additionally, the photothermal effect enhances blood-brain barrier permeability, improving the delivery of nanoparticle-based drugs to the brain. This chapter primarily focuses on the application of multi-target therapy using different photothermal agents to interfere with Aβ aggregation in AD treatment, as well as research exploring the use of the photothermal effect to cross the BBB. 4.1 Polymeric nanoparticles Polymer-based photothermal agents (PTAs) are gaining traction in AD therapy due to their tunable properties and strong near-infrared (NIR) absorption. These agents often feature a hydrophobic small-molecule core and are combined with hydrophilic polymers, lipids, or proteins to improve stability and biocompatibility [175]. The integration of photothermal effects with functional modifications has enabled these agents to disrupt Aβ aggregation effectively. Lai et al . [177] developed NIR-tunable polymer nanoparticles (PDLC NPs) to disaggregate Aβ aggregates via photothermal action. These nanoparticles encapsulate curcumin, an Aβ aggregation inhibitor, within a nanoscaffold made of PDPP3T-O14, a polymer with strong NIR absorption. A pentapeptide derived from the Aβ sequence was grafted onto PEG-lipid to enhance Aβ affinity, while thermally responsive phospholipids (e.g., DPPC) facilitated photothermal-triggered drug release (Figure 18a). Characterization using TEM, SEM, DLS, and UV spectroscopy confirmed high specificity for Aβ and excellent photothermal conversion efficiency. Under 808 nm laser irradiation, the nanoparticles disaggregated Aβ fibrils into amorphous aggregates, mitigating Aβ-induced neurotoxicity in PC12 cells through combined photothermal and anti-aggregation effects of curcumin (Figure 18b, c). Li et a l. [178] designed photothermal-responsive nanoparticles (NPs-C) to release curcumin, with PDPP as the photothermal agent. These spherical nanoparticles (40 nm) demonstrated a photothermal conversion efficiency of 57.54%, maintaining stability in buffer for 15 days. NPs-C effectively inhibited Aβ aggregation and disassembled Aβ fibrils under laser irradiation. The nanoparticles suppressed the TRPM2 ion channel, reducing intracellular calcium concentration and tumor necrosis factor-α levels, thereby mitigating neuroinflammation (Figure 25d). Xing et al . [179] also reported novel NIR-responsive nanoparticles synthesized via co-precipitation of GC5A, PEG-12C, and PDPP. These nanoparticles not only inhibited Aβ fibril formation but also disaggregated preformed fibrils under laser irradiation. In an AD mouse model, the nanoparticles reduced amyloid deposits in the hippocampus and showed enhanced BBB permeability post-laser irradiation, as evidenced by immunofluorescence imaging and ELISA. The synergistic action of nanoparticles and irradiation significantly reduced soluble and insoluble Aβ levels in the brain. Figure 18. a) Chemical structures and the synthesis of PDLC NPs. b) The inhibitory effect of PDLC NPs on Aβ42 fibrillation was confirmed by ThT, curcumin, PDLC, and DLC assays. c) TEM images of Aβ42 fibril in the absence or the presence of PDLC. d) Diagram depicting the synthesis of PEP NPs and their NIR light-triggered synergistic effects in inhibiting and disassembling Aβ fibrils.Aβ monomers aggregated into Aβ fibrils to damage nerve cells (red arrows). Aβ aggregation was inhibited to maintain Aβ monomers with the treatment of PEP NPs (blue arrow). After co-culture with PEP NPs, Aβ fibrils were disaggregated with or without irradiation (green arrow). e) Diagram of the synthetic route to BDP–HPC, with inset images displaying the solutions of BDP and BDP–HPC. f) The mechanism of DM-NCs and its activity in Aβ anti-aggregation/disaggregation. Zhang et al . [180] developed polypyrrole-based nanoparticles (PEP NPs) functionalized with an Aβ-targeting peptide (LVFFA-mPEG) and EGCG. Under 808 nm laser irradiation, the temperature of the nanoparticles rose from 35°C to 59°C, with a photothermal conversion efficiency of 24.6%. The nanoparticles disassembled Aβ fibrils through combined chemical and photothermal effects, reducing cytotoxicity and preserving cell membrane integrity (Figure 18d). Chen et al . [181] synthesized a biopolymeric PTT agent (BDP-HPC) using a boron dipyrromethene (BDP) scaffold integrated with hydroxypropyl cellulose (HPC). The agent demonstrated a photothermal conversion efficiency of 78.1% and strong photothermal and thermal stability over multiple cycles of NIR irradiation. BDP-HPC effectively inhibited Aβ42 aggregation and exhibited a potent photothermal dissociation effect on fibrillar aggregates(Figure 18e). Srivastava et al . [182] developed dopamine-melatonin nanocomposites (DM-NCs) that combine photothermal and pharmacological properties (Figure 18f). These self-assembled nanocomposites, activated by NIR irradiation, release melatonin and induce a photothermal effect that inhibits Aβ nucleation, self-seeding, and fibril propagation. DM-NCs effectively reduced intracellular Aβ production and aggregation in ex vivo AD models, highlighting their potential for multi-targeted therapy. Polymer-based photothermal agents exhibit significant promise in addressing Aβ pathology in AD through their ability to disrupt aggregation, mitigate neuroinflammation, and enhance BBB permeability. The ease of polymer modification allows for the design of multifunctional nanoparticles that integrate photothermal therapy with targeted drug delivery. These advancements offer a pathway toward more effective and non-invasive treatments for AD. 4.2 Inorganic photothermal nanoparticles Inorganic photothermal agents based on non-metallic materials include carbon (C), silicon (Si), and phosphorus (P). Among these, 2D graphene quantum dots (GQDs) are particularly notable for their unique characteristics, such as chemical stability, tunable reactivity, compatibility with heteroatom doping, low cytotoxicity, and adjustable water solubility. [183,184]. Meanwhile, metallic nanoparticles like silver, copper, platinum, and gold nanorods (AuNRs) are gaining attention in PTT due to their adjustable optical properties. Gold nanorods (AuNRs) generate heat when exposed to near-infrared (NIR) light, which allows for deep tissue penetration, making them highly suitable for photothermal therapy [185]. By controlling their size and aspect ratio (length-to-diameter ratio), the localized surface plasmon resonance (LSPR) of AuNRs can be easily tuned to the NIR region, enhancing their effectiveness as hyperthermal agents. Li et al . [186] used gold nanorods (AuNRs) as photothermal agents and conjugated Aβ15-20 (Ac-QKLVFF-NH2), a well-known Aβ-targeted peptide inhibitor, to the surface of AuNRs using polyoxometalates (POMs) as linkers (Figure 19a). This strategy aimed at delivering Aβ15-20 to effectively dissolve Aβ aggregates. AuP maintained Aβ aggregates as small, relatively amorphous forms, and under NIR laser irradiation, it could release Aβ15-20 to further inhibit Aβ aggregation. The photothermal effect of AuP enabled the disaggregation of Aβ fibril. Moreover, the inhibitory and disaggregation effects of AuP on Aβ aggregation and fibril disaggregation remained stable in mouse cerebrospinal fluid (CSF). Additionally, AuP, when pretreated with NIR irradiation in the presence of Aβ40, enhanced protection against apoptotic cell death. After tail vein injection of AuP into mice, the accumulation of AuP in the brain was detected to be about 2.097±0.337% six hours later, indicating the BBB permeability of AuP. Liu et a l. [187] and colleagues developed a smart theranostic nanoparticles (GAS) and which includes a targeting anti-Aβ scFv 12B4 and thermophilic acylpeptide hydrolase (APH). GAS utilizes surface plasmon resonance (LSPR) to monitor Aβ aggregation levels. Inhibiting Aβ monomer and oligomer aggregation, the presence of GNRs enhances the activity of APH, as the heat generated by AuNRs preserves the enzyme’s stability, which would otherwise be denatured or inactivated. Even after removal of GAS from the incubated solution, Aβ oligomers or fibrils did not reform for 7 days, indicating high clearance efficiency. As a result, GAS alleviated Aβ-induced neuronal cell death and improved motor function in AD nematode models expressing amyloid proteins in muscle cells. This approach, by combining gold nanorods with other nanomaterials, offers a strategy for developing functionalized photothermal agents to interfere with Aβ aggregation and related pathogenic factors in AD. Figure 19. a) Diagram showing peptide-conjugated Au nanorods designed for Alzheimer’s disease (AD) treatment. b) The mechanism of MoS₂/AuNR nanocomposites act as multifunctional inhibitors of Aβ fibrils for its strong near-infrared absorption. c) The NIR-responsive rPOMDs@MSNs@copolymer acting as a multifunctional PTT agent for AD treatment. d) The rPOMDs@MSNs@copolymer inhibit Aβ aggregation was verified by smaller ThT fluorescence intensity compared to in the absence NIR laser illumination. MoS2/AuNR [188] and KLVFF@Au−CeO2 (K-CAC) [110] nanocomposites have been reported for their ability to inhibit Aβ aggregation. MoS2 nanoparticles, in particular, are shown to alleviate Aβ-induced ROS and modulate amyloid aggregation. MoS2 nanosheets also demonstrate effects on the aggregation behavior of amyloids. Wang et al . discovered that under laser irradiation, MoS 2 /AuNR nanocomposites can modulate Aβ peptide aggregation, destabilize mature fibrils, and eliminate Aβ-induced ROS, effectively counteracting neurotoxicity. This makes MoS 2 /AuNR a promising approach for AD therapy, as it combines the photothermal effects of gold nanorods with the aggregation inhibition and ROS scavenging properties of MoS 2 (Figure 19b). Polyoxometalates (POMs) are known for their adjustable structure, excellent physicochemical properties, and good biocompatibility. Recently, reduced POMs (rPOMs), which exhibit strong near-infrared (NIR) absorption, have been developed as effective photothermal agents for tumor-specific treatment and photoacoustic imaging [189]. Qu et al . [190] introduced a redox-activated, NIR-responsive POMs-based nanoplatform (rPOMs@MSNs@copolymer), combining high photothermal effects with antioxidant properties (Figure 19c). In this system, poly(N-isopropylacrylamide-co-acrylamide) is used as a ”gatekeeper” to cap the channels of mesoporous silica nanoparticles (MSNs), preventing rPOMs leakage and ensuring stability during delivery. Upon 808 nm laser irradiation, local hyperthermia melts the poly(N-isopropylacrylamide-co-acrylamide) film, releasing rPOMs. These released rPOMs not only inhibit Aβ aggregation but also act as reducing agents to scavenge excess ROS. Additionally, rPOMs are oxidized into POMs by ROS, further contributing to the inhibition of Aβ aggregation, demonstrating their potential in AD therapy (Figure 19d). The rPOMs@MSNs@copolymer nanoplatform can generate local hyperthermia to disaggregate Aβ fibrils under NIR laser irradiation, thanks to the strong NIR absorption of rPOMs. Additionally, the antioxidant activity of rPOMs helps scavenge Aβ-induced ROS. rPOMDs@MSNs@copolymer under NIR laser irradiation significantly reduced the neurotoxicity of Aβ monomers and fibrils in co-culture with PC-12 cells. To further evaluate the physiological applicability of rPOMDs@MSNs@copolymer, the NPs were injected into mice via tail vein. After 12 hours, NPS was detected in the brain using ICP-MS, indicating that the NPs have the ability to cross the BBB. This work may pave the way for the development of multifunctional inorganic agents in biomedical applications. Thanks to the high photothermal conversion efficiency and strong absorption in the near-infrared (NIR) region, 2D transition-metal carbides and/or nitrides (MXenes) have demonstrated significant potential in various biomedical applications. Du and co-works [191] developed a 2D niobium carbide (Nb 2 C) MXene-based nano-chelator, called Nb 2 C MXenzyme, which not only inhibits copper-mediated Aβ aggregation but also acts as a nanomimetic enzyme with strong antioxidant activity (Figure 20a). In this study, Nb 2 C MXenzyme was first shown in vitro to bind copper ions and suppress Cu-Aβ aggregation, while also exhibiting superoxide dismutase (SOD)-like activity to scavenge ROS within cells. The photothermal effect of the nanozyme helped to open the BBB. Under NIR laser irradiation, Nb2C MXenzyme was effectively delivered to the brain of APP/PS1 transgenic mice, significantly improving cognitive function, as evidenced by water maze test results, which are commonly used to assess spatial cognition and memory in mice. Prussian blue nanoparticles (PB NPs), a type of metal-organic framework, possess strong near-infrared (NIR) light absorption and high photothermal conversion efficiency. These properties arise from the charge-transfer transitions between the iron redox pair Fe(II)/Fe(III) in the PB NPs structure. Additionally, PB NPs exhibit multiple enzyme-like activities, such as superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities, making them valuable for antioxidant therapy by removing ROS. Building on these properties, Song et al . [192] developed a peptide-modified PB NP (PBK NPs), where an 8-peptide sequence (CKLVFFAED), derived from the Aβ peptide, was conjugated to the PB NPs. This peptide has been identified as a recognition motif with a high affinity for binding to Aβ peptides as well as the extracellular V-domain of the receptor for advanced glycation end products (RAGE). This binding ability facilitates the delivery of PBK NPs across the BBB, where they can target the brain. PBK NPs demonstrate significant BBB-penetrating properties via RAGE binding and exhibit excellent antioxidant activity. When exposed to elevated hydrogen peroxide (H 2 O 2 ) levels, PBK NPs were shown to protect PC-12 cells by reducing ROS levels and mitigating apoptosis caused by oxidative stress. Furthermore, PBK NPs exhibit a higher Aβ binding affinity due to modified peptide (Figure 20b). The strong absorbance and excellent photothermal effect of PBK NPs under illumination enable the disintegration of Aβ fibril. Figure 20. a) Schematic diagram showing the construction of ultrathin Nb 2 C nanosheets and it have high BBB permeability under NIR-II irradiation for Cu 2+ capture and multiple enzyme-mimicking activities to scavenge ROS. b) Diagram depicting the suppression and breakdown of Aβ fibrillation along with the antioxidative capabilities of PBK NPs in AD therapy. c) U-CN/CoP synthesis and action mechanism. Carbon quantum dots (CQDs), with their abundant nitrogen-containing surface groups, effectively chelate Cu²⁺ ions, inhibiting Cu²⁺-mediated Aβ aggregation. Additionally, CQDs possess excellent photothermal properties, enabling them to act as PTT nanoagents. Under NIR light irradiation, CQDs generate localized hyperthermia, enhancing BBB permeability and dissolving Aβ amyloid deposits. Nitrogen-doped CQDs were synthesized using a one-pot method, followed by the extraction of cell membranes from macrophage RAW 264.7 cells [193]. The CQD-RAW composite was prepared through ultrasound-assisted mixing and incubation. CQDs efficiently captured excess Cu²⁺ ions and inhibited rapid Aβ aggregation, while their excellent photothermal properties allowed the dissolution of formed amyloid fibrils under NIR light. In vitro and in vivo studies demonstrated that the nanosystem significantly enhanced BBB permeability under laser irradiation, improving its ability to cross the BBB. 2D nanomaterials are highly effective in regulating Aβ self-assembly and influence fibrillation due to their unique properties, such as a large surface-area-to-volume ratio and surface charge. Silicene nanosheets (SNSs), as a novel 2D nanomaterial, exhibit excellent biocompatibility, biodegradability, high NIR absorption, and efficient photothermal-conversion capabilities, making them promising candidates for PTT. Liang et al . [165] synthesized SNSs using a combination of mild oxidation and liquid exfoliation methods. Circular dichroism spectra, fluorescence analyses, and nanostructure studies were employed to monitor and elucidate the photothermal degradation mechanism of mature Aβ33-42 fibrils. Moreover, PC12 cell viability exceeded 90% when incubated with SNSs under NIR irradiation, indicating improved biocompatibility and reduced phototoxicity towards PC12 cells. Ge et al . [194] combined the photothermal agent CoP with a doped g-C 3 N 4 upconversion photocatalyst to synthesize UCNP@g-C 3 N 4 /CoP (U-CN/CoP). CoP exhibits excellent optical absorption and photothermal conversion properties in the NIR region, while graphitized carbon nitride (g-C 3 N 4 ) demonstrates efficient catalytic activity for H 2 generation under visible light. Hydrogen (H 2 ), as an antioxidant, can selectively scavenge highly toxic ROS like •OH, offering therapeutic potential for AD. Additionally, CoP acts as a catalyst to accelerate the separation and transfer of photogenerated electrons in g-C 3 N 4 , enhancing the photocatalytic hydrogen evolution reaction. The metal ion-chelating ability of g-C 3 N 4 and the photothermal properties of CoP work together to inhibit Aβ aggregation and reduce Aβ deposition in the brain. In vivo studies confirmed that UCNP@g-C 3 N 4 /CoP effectively reduced Aβ deposition, alleviated memory impairment, and mitigated neuroinflammation in AD mice (Figure 20c). The development of advanced inorganic photothermal agents has significantly expanded the scope of AD therapy by integrating photothermal conversion, metal-ion chelation, ROS scavenging, and targeted Aβ inhibition. The versatility of these agents, particularly in their ability to cross the BBB and modulate multiple pathogenic pathways, underscores their potential in clinical applications. Future research should focus on optimizing their biocompatibility, stability, and therapeutic efficiency to pave the way for effective, non-invasive treatments for AD. Photopharmacology In previous sections, we discussed the unique advantages of light-responsive therapeutic strategies. However, both PTT and PDT inherently require the conversion of light energy into either singlet oxygen or thermal energy, which inevitably leads to interactions with biomolecules outside the pathological site. While researchers have made significant efforts to minimize these unintended effects—such as improving targeting specificity and designing drug release systems triggered by specific stimuli—these strategies cannot fully eliminate off-target interactions. If a specific molecule could be rendered light-sensitive, enabling direct and precise action on amyloid-beta proteins, it would allow light-based therapy to achieve precise spatiotemporal control while effectively leveraging its advantages without causing adverse side effects. Over the past decade, photopharmacology has evolved into a dynamic field. As the photophysical, pharmacodynamic, and pharmacokinetic properties of photoswitches, such as azobenzenes, have been well-established, their application has expanded to a variety of biological targets. Photoswitches are a class of compounds that display reversible photochemical behavior, enabling repeated transitions between active and inactive states. Various molecules display photoswitchable properties, including mechanisms such as ring-opening/closing and isomerization. The most widely used class of photoswitches for the photoregulation of biomolecules is azobenzene. This chapter provides a comprehensive review and summary of azobenzene’s applications in controlling amyloid-β aggregation for AD treatment. In 1937, Hartley et al . [195] provided evidence for the formation of cis -azobenzene by noting inconsistencies in absorbance measurements when azobenzene was exposed to light. Under irradiation at specific wavelengths, azobenzene undergoes a reversible transformation between its trans and cis isomers. This structural change significantly alters the end-to-end distance between the para-position carbons on its rings, with a variation of approximately 3.5 Å. In 2009, Hamill et al . [196] reported a study demonstrating the use of an azobenzene-based surfactant (azoTAB, 62 ) to regulate amyloid aggregation under light irradiation (Figure 21a). Small-angle neutron scattering (SANS) revealed that pure Aβ40 quickly form large 3D fibril networks with radii around 56 Å, and mesh sizes decrease from 1000 Å to 600 Å as aggregation progresses. With the azoTAB, cylindrical oligomers (46 Å diameter, 70 Å length) form initially, but larger fibrils (55 Å radius) eventually develop over time. This study demonstrates the potential of light-responsive azobenzene for regulating amyloid-beta aggregation. However, it does not explore its therapeutic prospects and instead shows that cis -AZOTAB accelerates fibril formation. It is important to note that trans -azobenzene is thermodynamically more stable, highlighting the significance of designing molecular frameworks where the cis -azobenzene structure specifically interacts with Aβ. Todd M. Doran et al . [197] synthesized an azobenzene β-hairpin mimetic (AMPP) to investigate the role of turn nucleation in Aβ self-assembly. They incorporated AMPP into the 25−27 region of Aβ42 as either a two- or three-amino acid substitution. Interestingly, the trans -AMPP Aβ42 conformer formed fibrillar structures nearly identical to wild-type Aβ42, including similar cytotoxicity. In contrast, the cis -AMPP Aβ42 congeners generated nonfibrillar, amorphous aggregates that were non-cytotoxic (Figure 21b). Furthermore, photoisomerization between cis and trans states enabled dynamic control over amyloid fibril formation, with cis -to- trans conversion rapidly producing native-like fibrils, while trans -to- cis switching reduced fibril populations. Figure 21. a) Chemical structures of azobenzene derivatives azoTAB, 61 . b) AMPP, 62 in the tran s (left) and cis (right) conformations and TME of fibrils derived from Aβ42, cis - 62 + Aβ42. c) Chemical formulas of the light-controlled molecular tweezers (LMTs) and selectively capture Aβ oligomers through changes in their spatial structure. Recently, Qian et al . [198] developed a light-controlled molecular clamp (LMTs) based on azobenzene, with two short peptides, KLVFF motifs, attached at both ends, which specifically bind to Aβ (Figure 21c). Utilizing the photoisomerization of azobenzene, the spatial distance between the KLVFF motifs is large in the trans -LMTs, while in the cis -LMTs, the distance between the groups becomes shorter, adopting a clamp-like configuration. This configuration enables the cis -LMTs to more easily bind smaller Aβ oligomers. To verify whether LMTs specifically bind Aβ oligomers, the authors synthesized biotin-labeled LMTs and captured the Aβ components bound to LMTs using biotin-streptavidin interaction, followed by gel chromatography for identification. Interestingly, cis -LMT1 specifically bound Aβ dimers, whereas trans -LMT1 showed almost no binding to oligomers. The use of cis -LMT1 to precisely capture and stabilize Aβ dimers reduced neuronal cell death induced by Aβ aggregation. Finally, under light exposure, cis -LMT1 captured and stabilized native Aβ dimers in AD nematodes, inhibiting Aβ aggregation, reducing its toxicity, and alleviating the movement disorders caused by Aβ aggregation. In conclusion, azobenzene, with its significant photo-responsive structural changes and extensive modifiability, holds great potential for AD therapy. Photobiomodulation PBM is a novel therapeutic technique that utilizes light to promote tissue repair and healing, with its efficacy supported by multiple studies. This approach involves the delivery of low-intensity red or near-infrared light to activate photoreceptors, thereby enhancing ATP synthesis, which subsequently improves cellular viability and metabolism [199-202]. In addition, PBM has been shown to mitigate oxidative stress, reduce inflammation, and decrease toxin accumulation through the activation of glial cells, providing further therapeutic benefits [203,204]. PBM has been explored as a potential intervention for various neurological disorders, including traumatic brain injury, Parkinson’s disease, and AD. Although it has not yet become a standard treatment, PBM offers the significant advantage of being non-invasive, thus avoiding many of the adverse effects commonly associated with conventional therapies [205,206]. Emerging evidence suggests that PBM enhances neuronal function, positioning it as a promising avenue for the development of innovative treatments for neurodegenerative diseases, particularly AD. Recent studies have provided evidence supporting PBM as a promising therapeutic strategy to control the progression of AD. Iaccarino et al. [207] treated 5xFAD mice with a non-invasive flickering light regimen and observed a reduction in Aβ levels in the visual cortex. Zhang and co-works. [208] found that 632.8 nm light therapy shifted APP processing toward a non-amyloidogenic pathway in APPswe/PS1dE9 (APP/PS1) mice, reducing Aβ production and plaque formation while improving memory and cognition. Grillo’s group [209] demonstrated that 1072 nm light therapy decreased Aβ protein levels in AD mouse models. Despite these promising effects, the underlying mechanisms of PBM remain largely unknown. In 2023, Mao et al . [210] highlighted the therapeutic potential of 1070 nm pulsed light (10 Hz) in modulating microglial phenotypes and mitigating Alzheimer’s disease (AD) pathology. The light-induced switch of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype was accompanied by the secretion of exosomes containing miR-7670-3p (Figure 22a). This microRNA targets activating transcription factor 6 (ATF6), a critical regulator of endoplasmic reticulum (ER) stress during the unfolded protein response. By downregulating ATF6, miR-7670-3p reduced ER stress and associated inflammation, thereby maintaining dendritic spine integrity and improving cognitive function in 5xFAD mice (Figure 22b). Additionally, therapy with 1070-nm light was associated with increased expression of postsynaptic proteins and reductions in ER stress, Aβ accumulation, and neuroinflammation, all of which are known contributors to synaptic deficits in AD. Suppression of the PERK/eIF2α pathway and neuroinflammation likely contributed to the restoration of synaptic plasticity and cognitive performance. Subsequently, they group [211] demonstrated that light therapy promoted mitochondrial metabolic homeostasis, which enhanced the functionality of meningeal lymphatic vessels (mLECs). This intervention restored the integrity of mLEC junctions, leading to improved lymphatic drainage and enhanced clearance of Aβ deposition and neuroinflammation. As a result, the pathology of AD was alleviated, and cognitive function was improved in AD mice. (Figure 22c). These findings underscore the role of exosomes derived from light-modulated microglia in ameliorating AD pathology and offer a theoretical foundation for near-infrared PBM as a promising therapeutic approach for AD. Figure 22. a) Exposure to 1070-nm light facilitates polarization of microglia from M1 to M2 in vivo . b) Representative 3D-reconstructed CA1 pyramidal neurons with Golgi staining among different groups. Scale bar = 50 µm. c) Near-infrared light enhances mitochondrial respiration, repairing lymphatic junctions, restoring mLV drainage, clearing Aβ, and alleviating neurodegeneration in mice. Current evidence indicates that PBM activates diverse signaling pathways in the brain, leading to a range of beneficial biological effects. Findings from experimental animal models and clinical trials have demonstrated its potential for managing AD with minimal side effects. As this promising therapy moves closer to clinical application, it is essential to transition PBM from preclinical research to practical use. However, further clinical trials are crucial to comprehensively evaluate its therapeutic efficacy and to establish standardized treatment protocols. These efforts could pave the way for innovative and safe strategies in the effective management of AD. Summary and perspectives Phototherapy has demonstrated potential in addressing AD through various mechanisms, including modulating Aβ aggregation and enhancing therapeutic outcomes. Despite significant progress, several critical challenges remain, requiring targeted research and innovation to facilitate clinical translation. 1. Tissue penetration depth One of the primary challenges in phototherapy is the limited tissue penetration depth of ultraviolet (UV) and visible light, making it difficult to target specific brain regions. While near-infrared (NIR) light has improved penetration capabilities, it still faces limitations when crossing the scalp and skull. Laser interstitial thermal therapy (LITT), guided by magnetic resonance imaging (MRI), has emerged as a potential solution and is in late-phase clinical trials for brain tumors. However, this approach requires invasive skull drilling and laser catheter insertion, posing risks and limiting widespread applicability. 2. Overcoming the BBB The BBB remains a significant obstacle in the diagnosis and treatment of AD, as it restricts the delivery of most therapeutic agents to the central nervous system. To improve BBB permeability, reducing molecular weight and enhancing lipophilicity in photoregulators could offer a solution. Additionally, developing nanomaterials with specific carriers targeting BBB receptors may increase therapeutic efficiency. Integrating photo-induced theranostic systems with targeted delivery mechanisms offers a promising approach for early-stage AD intervention. 3. Biocompatibility and safety considerations For clinical applications, the biocompatibility of phototherapeutic agents and light sources must be rigorously evaluated. Key considerations include: i) Designing non-toxic, stable, water-soluble, and biodegradable Aβ modulators. ii) Addressing the limitations of organic photosensitizers and nanomaterials, such as their cytotoxicity and genotoxicity. iii) Mitigating potential risks associated with reactive oxygen species (ROS)-induced cell damage and organ toxicity. iv) Light intensity must also be carefully optimized to ensure biosafety. The use of hetero-structured nanomaterials can enhance therapeutic efficiency while reducing off-target effects. Furthermore, advancements in Aβ-specific targeting and activatable nano-systems are needed to improve selectivity and minimize oxidative damage to healthy tissues. 4. Advancing PBM therapy PBM therapy has shown promise in preclinical models, but its efficacy in AD treatment remains to be validated through rigorous, randomized, double-blind clinical trials. To establish PBM as a mainstream therapy, high-quality evidence confirming its safety and efficacy is essential. Given the multifactorial nature of AD, integrating PBM with other therapeutic modalities and optimizing treatment protocols could lead to innovative management strategies. 5. Multifunctional modulators for complex AD pathology While phototherapy research has primarily focused on modulating Aβ aggregation, other pathological features such as tau hyperphosphorylation, dysregulated metal homeostasis, excessive ROS production, and neuroinflammation play pivotal roles in AD progression. Developing multifunctional modulators capable of combining Aβ inhibition with other therapeutic functionalities—such as metal chelation, ROS regulation, tau suppression, and anti-inflammatory effects—represents a critical next step toward effective AD-modifying therapies. 6. Expanding light-assisted and physical field-assisted therapies Light-assisted therapies, including PDT, PTT, and PBM, offer spatiotemporal control of Aβ aggregation. PDT and PTT enhance Aβ inhibitor effectiveness, while PBM minimizes their side effects. Additionally, other physical fields, such as ultrasound, magnetic, and electric fields, have shown potential in modulating Aβ fibrillization during AD progression. These approaches provide wireless, remote, and safe therapeutic strategies, meriting further investigation and development. Although phototherapy for AD is in its early stages, significant progress has been made in developing photo-responsive biomaterials for intensified modulation of Aβ aggregation and fibril elimination. The advancements discussed in this review lay a strong foundation for future research and innovation. It is foreseeable that non-invasive, light-facilitated strategies will become pivotal in the treatment of AD, offering safer and more effective therapeutic options for this challenging neurodegenerative disorder. Acknowledgements This work was financially supported by the National Natural Science Foundation of China (22293050, 22293051, 22377050, 92153303, 22477054), the Excellent Research Program of Nanjing University (ZYJH004), and the Natural Science Foundation of Jiangsu Province (BK20232020). References 1. Self WK, Holtzman DM. Emerging diagnostics and therapeutics for Alzheimer disease. Nat. Med . 2023 ;29(9):2187-2199. Crossref Google Scholar 2. Karran E, De Strooper B. 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Collection Aggregate Keywords alzheimer's disease phototherapy β-amyloid Authors Affiliations Yunhua Zhang Nanjing University School of Chemistry and Chemical Engineering View all articles by this author Chengyuan Qian State Key Laboratory of Pharmaceutical Biotechnology View all articles by this author Yuncong Chen 0000-0002-8406-4866 [email protected] Nanjing University School of Chemistry and Chemical Engineering View all articles by this author Weijiang He Nanjing University School of Chemistry and Chemical Engineering View all articles by this author Zijian Guo Nanjing University School of Chemistry and Chemical Engineering View all articles by this author Metrics & Citations Metrics Article Usage 611 views 328 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Yunhua Zhang, Chengyuan Qian, Yuncong Chen, et al. Phototherapy via modulation of β-amyloid in combating Alzheimer’s Disease. Authorea . 03 January 2025. 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