Authors
Shengjie Sun, Simin Wen, Ruiqi Zhang, Yanan Fu, Huisong Hao, You Li, Yingfei Wen, Ying Huo, Yixuan Fang, Shihao Zhuang, Jia Tang, Yanglong Hou, Tianqi Wang, Meiying Wu
Published in
Asian journal of pharmaceutical sciences. Volume 21. Issue 3. Pages 101171. Epub Jun 04, 2026.
Abstract
Cancer-associated fibroblasts (CAFs) are the primary source of collagen I, which contributes to the formation of a dense tumor extracellular matrix (ECM). Non-selective targeting of collagen I through CAF inhibition may inadvertently promote tumor cell detachment and metastasis by triggering anoikis resistance. To address this, a "wandering tumor cells" strategy is proposed, combining the induction of tumor cell deadhesion with the reversal of anoikis resistance. For heterologous targeted drug delivery, thermosensitive lipids and a photosensitizer are incorporated into M1-type macrophage membranes (TMs) to enable laser-responsive activation. Based on this approach, we designed a photothermally triggered, functional macrophage membrane-camouflaged nano-cracker (TM@cP/siF-ErN) with a particle size of 162.20 ± 0.54 nm for the co-delivery of erianin (Er) and focal adhesion kinase small interfering RNA (siFAK). Er is encapsulated in anisamide (AA)-modified nanodiscs (ErN) with hydrodynamic diameter of 15.07 ± 7.24 nm to selectively inhibit collagen I synthesis in CAFs by targeting pyruvate carboxylase, thereby inducing tumor cell deadhesion. siFAK is delivered to tumor cells using cinnamaldehyde-modified polyethyleneimine (cP/siF) to formed complexes with a particle size of 98.57 ± 1.47 nm and enhance transfection efficiency, enabling effective FAK knockdown and reversal of tumor anoikis resistance. Furthermore, TMs are fragmented into debris to amplify M2-type macrophage repolarization. Experimental results show that the nano-cracker efficiently targets orthotopic 4T1 breast tumors and, upon laser-triggered detonation, releases ErN, cP/siF and M1-type macrophage membrane fragments, which collectively promote tumor anoikis by suppressing collagen I synthesis in CAFs and reversing tumor cell anoikis resistance. Moreover, it promotes the repolarization of M2-type macrophages, which synergizes with collagen I downregulation-induced infiltration of CD8⁺ T lymphocytes to enhance the antitumor immune response, collectively resulting in pronounced breast cancer suppression. This nano-cracker implements the "wandering tumor cells" strategy, offering a promising approach for improving tumor therapy and enabling heterologous targeted delivery.
PMID:
42338758
Bibliographic data and abstract were imported from PubMed on 24 Jun 2026.
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