2. Academic Validation
  3. CXCR4-engineered fibroblast membrane nanovesicles for Photothermal-enhanced ferroptotic therapy through chemokine-navigated tumor homing

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

  • J Nanobiotechnology. 2025 Dec 30;24(1):102. doi: 10.1186/s12951-025-03951-5.
Lu Bai # 1 2 3,  Ya-Nan Tan # 4 5,  Li-Fen Zhang 1,  Min Luo 1,  Jie Luo 2 3,  Yu-Ma Yang 2 3,  Yun-Zhi Liu 1,  Victor Ho-Fun Lee 1 2 3,  Spring Feng-Ming Kong 1,  Xin-Yuan Guan 6 7 8 9
Affiliations

Affiliations

  • 1 Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong- Shenzhen Hospital, Shenzhen, China.
  • 2 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 3 State Key Laboratory of Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 4 Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong- Shenzhen Hospital, Shenzhen, China. [email protected].
  • 5 Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, China. [email protected].
  • 6 Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong- Shenzhen Hospital, Shenzhen, China. [email protected].
  • 7 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. [email protected].
  • 8 State Key Laboratory of Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. [email protected].
  • 9 Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, China. [email protected].
  • # Contributed equally.
PMID: 41462305 DOI: 10.1186/s12951-025-03951-5
Abstract

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 the translational potential of nanomedicine in clinical by developing precision nanomedicines that coordinate biological recognition with stimulus-responsive bioactivity.

Keywords

Chemokine-navigated targeting; Ferroptosis; Fibroblast membrane coating; Stimuli-responsive release.

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