Endoplasmic Reticulum-Targeted Polymer-Manganese Nanocomplexes for Tumor Immunotherapy

Manganese ions (Mn²⁺) are an immune activator that enhances the activation of both cGAS and STING proteins. The STING signaling activation and subsequential immune responses are predominantly associated with endoplasmic reticulum (ER). Therefore, ER targeting of Mn²⁺ in the subcellular compartments would promote the activation of STING signaling pathways. Herein, we report the design of ER-targeted manganese-based nanocomplexes (NCs) by complexation of Mn²⁺ with a zwitterionic polymer, poly[2-(N-oxide-N,N-dimethylamino) ethyl methacrylate] (OPDMA). The Mn/OPDMA nanocomplexes (Mn/OPDMA NCs) keep a long blood circulation for tumor accumulation and trigger adsorption-mediated transcytosis for extravasation and deep tumor penetration. Notably, in the tumor-associated macrophages, the Mn/OPDMA NCs can preferentially translocate to their ERs, significantly enhancing cGAS-STING pathway activation for tumor-associated macrophage polarization and IFN-β secretion. In mouse colon and hepatocellular cancer models, the intravenously administrated Mn/OPDMA NCs efficiently remodel tumor immune microenvironment, greatly retard tumor growths by 2.4- to 5-fold, and prolong the mouse survivals compared to free Mn²⁺-treated mice. This study provides the ER-targeted delivery of Mn²⁺ that achieves robust STING activation and, thus, potent systemic tumor inhibition without the toxicity of free Mn²⁺.