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

• Published in: Colloid and interface science communications Vol. 68; p. 100854
• Main Authors: Wang, Shouguang, Zhang, Xiaofei, Zhuang, Dunmin, Dong, Lina, Li, Bo
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.09.2025
• Subjects: Breast cancer; cGAS-STING pathway; Hyaluronic acid; Nanodelivery; Breast cancer; Hyaluronic acid; cGAS-STING pathway; Nanodelivery
• ISSN: 2215-0382; 2215-0382
• DOI: 10.1016/j.colcom.2025.100854

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 Mn2+-coordinated oxidized hyaluronic acid (OHA)-based nanoparticles co-loaded with phloretin (PHL) (OHA@Lys/PHL Mn2+). A nanosystem was engineered using oxidized hyaluronic acid (OHA) modified with lysine (Lys) to co-encapsulate PHL and Mn2+ 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. OHA@Lys/PHL Mn2+ 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 Mn2+ 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). This strategy offers a promising and clinically translatable approach for advanced breast cancer treatment. [Display omitted] •A novel OHA@Lys/PHL Mn2+ combines chemotherapy and immunotherapy for enhanced breast cancer treatment.•OHA@Lys/PHL Mn2+ significantly suppresses lung metastasis and immune evasion.•OHA@Lys/PHL Mn2+ induces DNA damage, ROS accumulation, and apoptosis while activating cGAS-STING pathway.