Targeting tumor microenvironment with biomimetic nanovesicles for non-small cell lung cancer gene therapy

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with therapeutic outcomes often constrained by the complexity of the tumor microenvironment (TME). Comprising diverse cell types and signaling molecules, the TME is increasingly recognized as a critical determinant of tumor behavior and patient prognosis. Cancer-associated fibroblasts (CAFs), a dominant TME component, drive progression through intercellular communication. Although CAF-targeted therapies hold promise, the precise mechanisms underlying CAF-cancer cell interactions remain elusive. Leveraging single-cell sequencing, we identified ACTN1 as a gene highly expressed in CAFs and strongly correlated with NSCLC prognosis. We engineered an integrated hybrid nanovesicle composed of CAF membranes (cM) and a liposome core to encapsulate siRNA against ACTN1 (siACTN1). This represents the first CAF-membrane-coated siRNA system targeting ACTN1 for NSCLC therapy. The nanovesicles modulate cytokine secretion (IL-6 and CCL2) to inhibit NSCLC cell growth, migration, and invasion in vitro. In vivo studies corroborated these findings, demonstrating reduced cytokine secretion and attenuated tumor growth. By harnessing the intrinsic properties of CAFs for targeted siRNA delivery, these nanovesicles offer a novel strategy for TME modulation in NSCLC.