A MnO2-based tumor-seeking nanoplatform for enhanced chemoimmunotherapy against 4T1 breast cancer

A significant obstacle in oncological therapy lies in surmounting the immunosuppressive microenvironment while enhancing the anti-tumor efficacy of chemotherapeutic agents. STING agonists such as Mn²⁺ have demonstrated substantial promise in this regard. Squamocin (Squ), a naturally derived compound, exhibits potent anti-tumor activity with minimal drug resistance; however, its application is hampered by poor water solubility (approximately 7.5 μg/mL) and off-target toxicity. In this study, a chemo-immunotherapy approach utilizing MnO₂ nanoparticles combined with squamocin (Squ) has been formulated, with its therapeutic effectiveness further augmented through surface modification with the tumor-targeting IR820 molecule. The intravenously injectable MnO₂ nanoparticles were synthesized from KMnO₄ and anhydrous ethanol, and subsequently modified with Astragalus polysaccharides (APS)-IR820 on their surface to improve stability in physiological media and facilitate tumor targeting and <i>in vivo</i> fluorescence imaging. The resultant MnO₂@APS-IR820 NPs, measuring 193.4 ± 1.7 nm, generated Mn²⁺ in response to the elevated glutathione (GSH) levels within the tumor microenvironment. The generated Mn²⁺ notably induced maturation of bone marrow dendritic cells (BMDCs) and promoted the repolarization of tumor-associated macrophages from the pro-tumor M2 phenotype to the anti-tumor M1 phenotype. When combined with Squ@APS-IR820 NPs (220.1 ± 11.2 nm in size), the chemoimmunotherapy significantly stimulated both innate and adaptive immune responses in a 4T1 tumor bearing mouse model and demonstrated a synergistic anti-tumor effect, achieving a tumor inhibition rate of approximately 92 %, highlighting its remarkable potential for anti-tumor therapy.