Neutrophil-excluding nanoparticles abrogate biomechanical and immunological barriers to sensitize radioimmunotherapy

Desmoplastic tumors are highly resistant to treatment, largely due to their dense fibrotic stroma. Paradoxically, radiotherapy (RT) exacerbates this challenge by triggering a pro-fibrotic and immunosuppressive cascade. Here, we identify an RT-induced neutrophil-fibroblast-macrophage hierarchy as a key driver of this therapeutic resistance. To circumvent this barrier, we developed a nano-modulator, termed NanoNex, to precisely intervene in this cellular crosstalk. By transcriptionally inhibiting post-RT neutrophil recruitment via SMAD3 suppression, NanoNex effectively abrogates neutrophil-dependent stromal deposition and alleviates biomechanical tension. Crucially, this remodeling of the tumor microenvironment restores macrophage plasticity and unlocks their responsiveness to immune adjuvants, enabling potent M1 polarization. In refractory murine models of pancreatic and breast cancer, NanoNex markedly potentiated radioimmunotherapy, eliciting robust tumor regression. Furthermore, NanoNex induced systemic anti-tumor immune memory in the pancreatic cancer model. Collectively, our findings demonstrate that this nano-enabled neutrophil exclusion strategy serves as a transformative platform to normalize the biomechanical and immunosuppressive tumor microenvironment, converting RT-induced stromal barriers into a permissive landscape for effective radioimmunotherapy.