Melanin-Based Immunoregulatory Nanohybrids Enhance Antitumor Immune Responses in Breast Cancer Mouse Model.

Abstract

Natural melanin nanoparticles (MNPs) have demonstrated a potential for eliciting antitumor immune responses through inducing immunogenic cell death (ICD); however, the tumor microenvironment (TME) has been shown to inhibit T cell-mediated antitumor immunity. To address this challenge, we designed TME-responsive biodegradable melanin/MnO_<i>x</i> nanohybrids via a biomineralization process. Under near-infrared (NIR) light irradiation, the photothermal property of melanin/MnO_<i>x</i> nanohybrids triggers ICD and release of tumor-associated antigens (TAAs), while Mn²⁺ and TAAs induce dendritic cell (DC) maturation to provoke immune responses. Furthermore, the immunoregulatory properties of the nanohybrids themselves are exploited to reshape immunosuppressive TME and downregulate PD-L1 through alleviation of the hypoxic and acidic TME. Although MNPs demonstrate higher photothermal killing efficiency than the nanohybrids <i>in vitro</i> due to their superior photothermal effect, the melanin/MnO_<i>x</i> nanohybrids exhibit significantly enhanced antitumor and antimetastatic effects <i>in vivo</i>, benefiting from their ability to reverse immunosuppression and induce DC maturation. Transcriptomics analysis confirmed the successful activation of immune responses. This work presents a promising approach for immunomodulation-enhanced cancer therapy through the intrinsic properties of melanin/MnO_<i>x</i> nanohybrids.