An inhalable liquid-core lipid nanoplatform enables macrophage-mediated mRNA delivery to lung tumors.

Immunotherapeutic failures in non-small cell lung cancer (NSCLC) and other solid tumors are often attributed to tumor-induced T cell dysfunction. However, current treatments frequently fail to initiate a complete cancer-immunity cycle within the immunosuppressive tumor microenvironment (TME). Inspired by intercellular RNA transfer mediated by extracellular vesicles (EVs), we developed an inhalable nanoplatform (p53 mRNA/lipid liquid nanoparticle complex, known as LLX) to "relay" delivery of p53 mRNA from tumor-associated macrophages (TAMs) to NSCLC cells, overcoming the challenges posed by passive diffusion and size limitations within the solid TME. After inhalation in a lung orthotopic tumor model, LLX uniformly dispersed throughout the lung airways and markedly boosted LLX-EV production by TAMs. This in vivo strategy of generating endogenous EVs loaded with exogenous mRNA not only induced p53-mediated apoptosis in NSCLC cells but also fundamentally reshaped the TME by directly modulating the TAM phenotype and alleviating T cell exhaustion. Our results show that p53 mRNA/LLX resulted in sustained tumor regression, underscoring its potential to expand the therapeutic scope of gene immunotherapy by effectively tackling key challenges in solid tumor treatment, such as immunosuppression and the limited transfection efficiency of mRNA.