Abstract
The cGAS-STING pathway holds tremendous potential as a regulator of immune responses, offering a means to reshape the tumor microenvironment and enhance tumor immunotherapy. Despite the emergence of STING agonists, their clinical viability is hampered by stability and delivery challenges, as well as variations in STING expression within tumors. In this study, we present Mn-phenolic networks as a novel carrier for ADU-S100, a hydrophilic STING agonist, aimed at bolstering immunotherapy. These nanoparticles, termed TMA NMs, are synthesized through the coordination of tannic acid and manganese ions, with surface modification involving bovine serum albumin to enhance their colloidal stability. TMA NMs exhibit pH/GSH-responsive disintegration properties, enabling precise drug release. This effectively addresses drug stability issues and facilitates efficient intracellular drug delivery. Importantly, TMA NMs synergistically enhance the effects of ADU-S100 through the concurrent release of Mn2+, which serves as a sensitizer of the STING pathway, resulting in significant STING pathway activation. Upon systemic administration, these nanoparticles efficiently accumulate within tumors. The activation of STING pathways not only induces immunogenic cell death (ICD) in tumor cells but also orchestrates systemic remodeling of the immunosuppressive microenvironment. This includes the promotion of cytokine release, dendritic cell maturation, and T cell infiltration, leading to pronounced suppression of tumor growth. Combining with the excellent biocompatibility and biodegradability, this Mn-based nanocarrier represents a promising strategy for enhancing tumor immunotherapy through the cGAS-STING pathway.