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Nano-mechanochemical synergistic approach to reprogram tumor-associated macrophages for tumor immunotherapy

Xiaoyou Zhang,Zichen Yang,Hui Zhi,Shiyu Chen,Weimin Yin,Lulu An,Rongjie Li,Yanni Cai,Caoyi You,Haiqing Dong,Yongyong Li,Yan Li

Tumor-associated macrophages (TAMs) play a crucial role in tumor progression and therapy resistance. The mechanochemical synergy has emerged as a key mechanism regulating the polarization of TAMs toward the tumor-promoting M2 phenotype. However, whether this synergy can be exploited to reprogram TAMs to a tumor-suppressive M1 phenotype remains an unexplored therapeutic strategy. Here, we report a mechanochemically synergistic nanoplatform, RMSN@EXO, designed to reprogram TAMs efficiently and enhance the anti-tumor immune microenvironment. This nanoplatform is composed of mesoporous silica nanoparticles (MSNs) with tailored elasticity and is loaded with the immunomodulator resiquimod (R848). Both MSNs and R848 were identified through screening based on the M1-specific metabolic marker, lactate. And RMSN is subsequently encapsulated within exosomes derived from M1 macrophage. Surprisingly, this nanoplatform efficiently reprograms TAMs into a pro-inflammatory M1-phenotype more effectively than either R848 or MSNs alone. Benefiting from the superior penetration of mechanically tailored MSNs in the TME and the exosome-mediated tumor targeting, RMSN@EXO exhibits enhanced accumulation in hypoxic regions of solid tumors. In vivo experiments further show that repolarized TAMs in hypoxic areas have a significant inhibitory effect on tumor growth. In conclusion, this study establishes a “nano-mechanochemical synergy” strategy to efficiently reprogram TAMs to enhance robust anti-tumor immunity. It provides a fundamental framework for designing nanomedicines based on mechanical properties to improve cancer immunotherapy.