CXCR4-engineered fibroblast membrane nanovesicles for Photothermal-enhanced ferroptotic therapy through chemokine-navigated tumor homing

作者：Lu Bai, Tan Ya-nan, Li-fen Zhang, Min Luo, Jie Luo, Yu-Ma Yang, Yunzhi Liu, Victor Lee, S. Kong, Xin-Yuan Guan · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03951-5 · 被引用次数：2 · 研究领域：Nanoplatforms for cancer theranostics、Chemokine receptors and signaling、Extracellular vesicles in disease

BACKGROUND: Cell membrane-camouflaged nanoparticles (NPs) have attracted increasing attention for cancer-targeted drug delivery, but their clinical translation faces critical challenges due to the biosafety concerns and scalability issues. Dermal fibroblasts are an abundant, clinically accessible membrane source, and genetic programmability offers a route to active homing. RESULTS: We engineered fibroblast membrane nanovesicles from dermal fibroblasts overexpressing CXCR4 to actively home toward CXCL12-enriched tumor microenvironments. These CXCR4-engineered membrane nanovesicles demonstrated tumor-selective accumulation in multiple preclinical models with high CXCL12 secretion. The near-infrared (NIR) photosensitizer IR780 and the ferroptosis inducer RSL3 were co-loaded to form FbM@IR/RSL3 NPs for photothermal-controlled ferroptosis therapy. Upon NIR irradiation, FbM@IR/RSL3 NPs generated localized photothermal heating and simultaneously triggered RSL3 release. The combination of glutathione peroxidase 4 (GPX4) inhibition and iron-catalyzed lipid peroxidation amplified ferroptotic tumor cell death. In vivo studies reveal enhanced tumor suppression across heterogeneous carcinoma models compared to monotherapy approaches, with systemic biocompatibility confirmed by comprehensive hematological and histopathological analyses. CONCLUSIONS: Fibroblast membrane engineering, combined with chemokine-gradient navigation and photothermally controlled therapeutic activation, represents ...