A safe saponin-based nano-strategy for manganese-mediated STING activation

The effective delivery of hydrophilic therapeutic agents (e.g., transition metal ions and protein antigens) remains a significant pharmacological hurdle in immunotherapy. Saponin-based delivery platforms demonstrate remarkable potential. Therapeutic modulation of the cGAS–STING pathway using manganese ions (Mn²⁺) holds significant promise for cancer immunotherapy. However, clinical translation faces additional safety challenges beyond delivery issues, since therapeutic doses of Mn²⁺ often induce chronic inflammation and oxidative stress. To address these challenges, we developed a biomimetic nanoparticle, Human serum albumin-Astragaloside IV-MnCl₂ nanoparticles(HSA–A–M NPs), leveraging the dual functionality of the saponin astragaloside IV (AS-IV). AS-IV enhances Mn²⁺ uptake by increasing membrane permeability while suppressing NF-κB-driven inflammation and ROS production, improving safety. The nanoparticle's core, stabilized by HSA, boosts biocompatibility, while surface modifications with chitosan and hyaluronic acid (HA) derivatives (CS-NG@HGS) optimize tumor targeting, yielding the final formulation CS–NG@HGS@HSA–A–M. In vitro and vivo, this platform enhances cGAS–STING-mediated antitumor immunity while minimizing systemic Mn²⁺ toxicity and inflammation. By combining Mn²⁺ delivery with AS-IV's anti-inflammatory effects, it establishes a “controlled-activation” paradigm—potentiating IFN-I production yet curbing excessive immune responses. This dual-action design offers a safer, adaptable framework for metal ion-based combination therapies.