Photothermal-detonated functional macrophage membrane-camouflaged nano-crackers induce tumor cell wandering-anoikis

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.