Photoactivated Hypericum perforatum-Derived Exosome Nanovesicles Suppress Breast Cancer via miR-172f/CD24-Siglec-G/10-Driven Macrophage Reprogramming.

Photodynamic therapy is traditionally based on reactive-oxygen-species-mediated tumor cell killing, but its immunomodulatory capacity is not fully explored. Plant-derived exosome-like nanovesicles provide a natural photosensitizer platform with potential for dual tumoricidal and immune-modulating effects. This study investigated whether light activation of Hypericum perforatum-derived exosome nanovesicles (HPDENs) remodels their microRNA cargo to enhance antitumor activity and reprogram the tumor immune microenvironment. Photoactivation significantly up-regulated miR-172f-p3 in HPDENs, which directly targeted CD24 messenger RNA and suppressed its expression in MCF-7 cells. CD24 down-regulation reprogrammed co-cultured M2 macrophages toward an M1 phenotype by attenuating the CD24-Siglec-G/10 axis. In vivo, light-treated HPDENs and miR-172f-p3 mimics inhibited tumor growth, promoted M1 polarization, and displayed excellent safety with no observable systemic toxicity. Photoactivated HPDENs exert dual antitumor effects by inducing direct tumor suppression and remodeling the immune microenvironment through miR-172f-p3/CD24-Siglec-G/10 signaling. This strategy offers a novel immunotherapeutic avenue that synergizes with photodynamic therapy, supporting the development of plant-derived nanovesicles as next-generation cancer therapeutics.