Endocytic Programming via Porous Silicon Nanoparticles Enhances TLR4 Nanoagonist Potency for Macrophage‐Mediated Immunotherapy

Abstract Proinflammatory repolarization of tumor‐associated macrophages (TAMs) positively correlates with improved therapeutic outcomes in non‐small cell lung cancer (NSCLC), positioning TAM‐targeted immunotherapy as a promising strategy. Here, porous silicon nanoparticles (PSiNPs) are reported that enhance macrophage internalization of manganese@albumin nanocomplexes (M‐BSA), driving an endocytic shift from phagocytosis to clathrin‐mediated endocytosis. This endocytic programming facilitates the trafficking and endosomal aggregation of membrane‐anchored toll‐like receptor 4 (TLR4), redirecting downstream signaling toward the toll/interleukin‐1 receptor domain‐containing adaptor‐inducing interferon‐β (TRIF)‐biased pathway to trigger robust proinflammatory responses. Compared to free M‐BSA, M‐BSA@PSiNPs significantly elevate macrophage secretion of tumor necrosis factor‐α (TNF‐α), enhancing cytotoxicity against NSCLC cells in vitro. Combined with immune checkpoint blockade therapy, M‐BSA@PSiNPs synergistically repolarize TAM and remodel the immunosuppressive tumor microenvironment, resulting in potent eradication of established NSCLC tumors in vivo. These findings highlight the potential of M‐BSA@PSiNPs as a TLR4 nanoagonist platform for TAM‐mediated immunotherapy against NSCLC.