Self-assembled supramolecular nanoparticles of α-mangostin for targeted STING activation and enhanced tumor immunotherapy

Targeted activation of the stimulator of interferon genes (STING) signaling pathway represents a promising strategy to counteract immunosuppressive tumor microenvironments (TME) and elicit anti-tumor immunity. However, clinical translation of STING agonists has been strongly hindered by the challenges in achieving tumor-targeted STING activation. Here, we report a facile and efficient supramolecular self-assembly strategy for tumor-targeted STING activation of α-mangostin (MGT), a natural non-cyclic dinucleotide STING agonist. MGT can self-assemble into uniform supramolecular nanoparticles (MGT-SNPs) with 100% drug loading, driven by its inherent amphiphilic xanthone structure via multiple non-covalent interactions. The resulting MGT-SNPs (∼186.50 nm, negatively charged) demonstrate excellent colloidal stability, pH-responsive drug release, and enhanced cellular uptake in vitro. Furthermore, MGT-SNPs exhibit sufficient circulatory stability, enabling efficient tumor accumulation and cytosolic delivery via the enhanced permeability and retention (EPR) effect. Leveraging these favorable properties, MGT-SNPs enhance STING activation both in vitro and in vivo, effectively remodeling TME. Consequently, MGT-SNPs trigger robust anti-tumor immunity in melanoma-bearing mice following either intratumoral or intravenous administration. Collectively, this work showcases a supramolecular self-assembly strategy based on the intrinsic structural properties of a STING agonist for tumor-targeted STING activation, which eliminates carrier-related toxicity and offers a clinically promising approach for STING-targeted cancer immunotherapy.