Tumor pH-triggered PEG detachable nanoparticles for TLR7/8 agonist delivery to improve cancer immunotherapy

Antigen-presenting cells (APCs), such as macrophages and dendritic cells (DCs) are key players in modulating the immune responses of cytotoxic T lymphocytes (CTLs). Resiquimod (R848), a toll-like receptor (TLR) agonist, has demonstrated the capacity to enhance APC function and reprogram the phenotype of macrophages; however, the unfavorable in vivo performance constrains its therapeutic potential. Here, we developed R848-loaded mesoporous silica nanoparticles (denoted as R848@MSN-bi-PEG) with pH-responsive surface polyethylene glycol (PEG) detachment to effectively modulate APCs. The acidic tumor pH triggered PEG detachment when R848@MSN-bi-PEG accumulated at the tumor site, thereby promoting APC uptake and R848 release, which facilitated DCs maturation and macrophage repolarization to a pro-inflammatory phenotype. The in vivo antitumor study indicated that R848@MSN-bi-PEG led to potent anti-tumor immunity by modulating the immunosuppressive tumor microenvironment. This approach offers a novel strategy to improve the effectiveness of cancer immunotherapy.