Calcium-triggered self-anchoring bilayer microneedle patch with spatiotemporally programmed TLR4 activation remodels the immune microenvironment of abdominal wall endometriosis

Siqi Chen, Jinhua Zhou, Ting Zhang, Yonggang Li, Xinyu Liu, Yu Chen, Haowen Lu, Minbo Jian, Zheming Shen, Xinzhi Liang, Yusen Qiao, Youguo Chen
In: Chemical Engineering Journal · 2026 · pp. 183469 · doi:10.1016/j.cej.2026.183469 · W7223449562
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A calcium-triggered bilayer microneedle patch sequentially activates TLR4 to shift abdominal wall endometriosis macrophages from M1 to M2, inhibiting lesion growth and fibrosis in mice without systemic toxicity.

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Abstract

Abdominal wall endometriosis (AWE), a distinct clinical subtype of endometriosis, is driven by a dysregulated immune microenvironment dominated by M2 macrophages. Current surgical and hormonal therapies are limited by high recurrence (5–20%), incomplete lesion resection, systemic side effects, and unsuitability for fertility-seeking patients. Here, we design a calcium-triggered self-anchoring bilayer microneedle patch (d-MN@DDAH) that integrates mechanical interlocking, pH-responsive drug release, and spatiotemporally programmed immunomodulation for a “first attack, then repair” AWE therapy. The lower needle layer consists of oxidized alginate grafted with a TLR4-targeting peptide (DDAH) via Schiff base bonds for acid-responsive immune activation; the upper layer comprises gelatin methacryloyl loaded with citric acid (CA) for sustained repair. The patch exhibits a well-defined bilayer structure, sufficient mechanical strength for skin penetration, and calcium-triggered swelling for tissue anchoring. DDAH shows pH-dependent release, while CA displays sustained release over 14 days. The patch is non-cytotoxic and orchestrates sequential macrophage polarization from an early M1 phenotype to a reparative M2 phenotype in vitro. In vivo dynamic monitoring further confirmed an early M1-dominant phase followed by a timely M2 transition. This reprogrammed microenvironment inhibits endometriotic cell proliferation and invasion, induces apoptosis, and downregulates key pathogenic molecules including MMP-2/9 and CYP19A1. In an AWE mouse model, the d-MN@DDAH patch achieves 92.6% lesion growth inhibition, reduces fibrosis, restores immune homeostasis (M1/M2 ≈ 0.62:1), alleviates pain, and shows no systemic toxicity. This work provides a transformative, non-hormonal, and spatiotemporally programmable platform for AWE and other immune-mediated diseases.

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