M1 Macrophage-Derived Extracellular Vesicles Enable Efficient Cytosolic Delivery of siRNA to Suppress Lung Squamous Cell Carcinoma
Huan Li, Yuanmei Lou, Jun Chen, Qichen Huang, Chaowu Liu, Zhijun ChenAbstract
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.