A triple-immunomodulatory quercetin nanoplatform to reinforce T-cell function and remodel tumor microenvironment

Immune checkpoint inhibitors (ICIs) often exhibit limited clinical efficacy due to insufficient infiltration of T cells in the tumor microenvironment (TME). To address this challenge, we utilized quercetin, an active ingredient of traditional Chinese medicine, as an alternative ICI, and developed a hyaluronic acid-coated manganese-embedded mesoporous silica nanoparticle (HA-MSN(Mn) for TME-triggered co-delivery quercetin (Que) and Mn²⁺ to potentiate cancer immunotherapy. This nanoplatform exploits the dual pH/redox-responsive MnO bond cleavage within the TME, triggering structural disintegration of the nanoparticles and subsequent controlled release. Through in vitro and in vivo models, we demonstrated that this nanoplatform employs a triple immunomodulatory mechanism to enhance T-cell function and reverse the immunosuppressive TME. Specifically: (1) both Que and Mn²⁺ could independently promote dendritic cell (DC) maturation, contributing to T-cell activation; (2) Mn²⁺ and Que could independently facilitate M1 macrophage polarization, thereby recruiting T cells to tumors by secreting immune cytokines; (3) Que loaded HA-MSN(Mn) downregulates PD-L1 expression on tumor cells, overcoming immune escape and enhancing T cell cytotoxicity. Furthermore, the nanoplatform exhibits antitumor effects associated with immune modulation, alongside enhanced inhibition of tumor growth, with minimal off-target toxicity. Importantly, this study provides deeper insights into the multi-immunomodulatory role of quercetin, offering a promising nanotechnology-driven approach for immunotherapy.