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.