M1 Macrophage-Derived Extracellular Vesicles Enable Efficient Cytosolic Delivery of siRNA to Suppress Lung Squamous Cell Carcinoma

Abstract Lung squamous cell carcinoma (LUSC) remains a clinically challenging malignancy with limited targeted therapies. We previously reported Sugen kinase 495 (Sgk495) overexpression in LUSC and its pro-tumorigenic functions. However, efficient cytosolic delivery of Sgk495 siRNA to LUSC cells remains a major obstacle. Here, we engineered biomimetic nanoscale extracellular vesicles (EVs, ∼130 nm) derived from M1-polarized macrophages and loaded them with Sgk495 siRNA (M1 EV/siSgk495) as a targeted nanomedicine for LUSC therapy. Compared with M0 EVs and conventional liposomal nanocarriers, M1 EVs exhibited superior siRNA stability. Mechanistically, M1 EV/siSgk495 downregulated Sgk495, disrupted its interaction with E3 ligase COP1, reduced K48-linked polyubiquitination and proteasomal degradation of IFNGR1, and thereby upregulated IFNGR1 protein. Collectively, this M1 macrophage-derived EV nanoplatform inhibits LUSC via IFNGR1 stabilization, representing a promising biomimetic nanotherapeutic strategy for cytosolic RNAi-based treatment of LUSC.