Mn2+-coordinated hyaluronic acid modified nanoparticles for phloretin delivery: Breast cancer treatment

Objective Breast cancer remains a global health challenge due to limitations of conventional therapies, such as drug resistance and systemic toxicity. This study aimed to develop a novel synergistic chemo-immunotherapy platform by constructing Mn 2+ -coordinated oxidized hyaluronic acid (OHA)-based nanoparticles co-loaded with phloretin (PHL) (OHA@Lys/PHL Mn 2+ ). Methods A nanosystem was engineered using oxidized hyaluronic acid (OHA) modified with lysine (Lys) to co-encapsulate PHL and Mn 2+ ions. The anti-tumor efficacy was evaluated in vitro (4 T-1 breast cancer cells) and in vivo (4 T-1 tumor-bearing mice), including assessments of proliferation inhibition, apoptosis induction, reactive oxygen species (ROS) accumulation, DNA damage, cGAS-STING pathway activation, and dendritic cell (DC) maturation. Combination therapy with cisplatin (CDDP) was also investigated. Results OHA@Lys/PHL Mn 2+ achieved 80.3 % cell viability inhibition on 4 T-1 cells. Combined with CDDP, it further suppressed proliferation, induced apoptosis, and enhanced ROS accumulation. Mechanistically, the nanosystem induced DNA double-strand damage and activated the cGAS-STING pathway. In vivo , OHA@Lys/PHL Mn 2+ monotherapy showed significant tumor inhibition (46.4 %, p  < 0.001). Combination with CDDP achieved near-complete tumor suppression (86.7 % inhibition) and reduced lung metastasis. The in vivo mechanism results indicated that nanosystem triggered DNA damage, activated cGAS-STING signaling, and significantly promoted DC maturation (48.5 % vs. 28.2 % in controls). Conclusion This strategy offers a promising and clinically translatable approach for advanced breast cancer treatment.