Manganese Oxide-Based Multifunctional Nanoplatform for Synergistic Therapy of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) presents low bioavailability and high resistance to poly (ADP-ribose) polymerase inhibitors (PARPi), posing formidable therapeutic challenges. The development of a multifunctional nanotheranostic platform for TNBC therapy is desirable. Herein, leveraging the structural versatility of manganese-based nanoarchitectures, we developed manganese oxide-based nanoparticles (NPs) loaded with the PARPi olaparib (OLA) as a multifunctional nanotheranostic platform (OLA-MnO2@PDA NPs). These NPs degrade responsively in the tumor microenvironment (TME), concurrently releasing OLA and Mn2+, which initiates a self-amplifying cascade of antitumor effects. Released OLA inhibits DNA damage repair, driving genomic instability and substantial DNA fragmentation. Simultaneously, Mn2+ induces reactive oxygen species production for chemodynamic therapy (CDT), further exacerbating DNA damage. Notably, cytosolic DNA fragments synergize with Mn2+ to potently activate the cGAS-STING pathway, driving type I interferon responses and augmenting tumor immunogenicity. Additionally, the generated oxygen alleviates tumor hypoxia and remodels aberrant tumor metabolism by downregulating HIF-1α and its downstream glycolytic enzymes (HK2 and PKM2). This integrated strategy of immunotherapy, CDT, and metabolic intervention substantially boosts antitumor efficacy. Moreover, responsive "turn-on" T1-weighted magnetic resonance imaging enables real-time treatment monitoring. Overall, OLA-MnO2@PDA NPs represent a promising synergistic platform for TNBC therapy with significant clinical translation potential.