Targeted Delivery of STING Agonist via Albumin Nanoreactor Boosts Immunotherapeutic Efficacy against Aggressive Cancers

<b>Background:</b> Activating the cytosolic innate immune sensor, the cGAS-STING pathway, holds great promise for enhancing antitumor immunity, particularly in combination with immune checkpoint inhibitors (ICIs). However, the clinical application of STING agonists is often hindered by poor tumor accumulation, limited cellular uptake, and rapid clearance. To address these challenges, we developed a human serum albumin (HSA)-based nanoreactor system for the efficient delivery of the STING agonist SR-717, aiming to improve its antitumor efficacy. <b>Methods:</b> Using a biomineralization technique, we encapsulated SR-717 within HSA nanocages to form SH-NPs. These nanoparticles were characterized in terms of size, stability, and cellular uptake, and their ability to activate the STING pathway was assessed in both in vitro and in vivo models, including freshly isolated human renal tumor tissues. In vivo antitumor efficacy was evaluated in a murine renal tumor model, and immune responses were measured. <b>Results:</b> SH-NPs exhibited enhanced stability, efficient cellular uptake, and superior tumor accumulation compared to free SR-717. They robustly activated the STING pathway, as evidenced by increased phosphorylation of TBK1 and IRF3, along with elevated IFN-β production. Additionally, SH-NPs reshaped the immunosuppressive tumor microenvironment, promoting T-cell-mediated immunity and improving the therapeutic efficacy of checkpoint blockade in murine models. The validation in human renal tumor tissues further highlighted their potential for clinical translation. Importantly, SH-NPs were well tolerated with minimal systemic toxicity. <b>Conclusions:</b> This study underscores the potential of HSA-based nanoparticles for the targeted delivery of STING agonists, effectively enhancing antitumor immunity and improving cancer immunotherapy outcomes. SH-NPs offer a promising solution to the limitations of current STING agonists in clinical settings.