Dual‐targeted nanomedicine delivering doxorubicin and nitric oxide for tumor immunomodulation and synergistic therapy

Abstract Cancer therapeutic efficacy is significantly influenced by tumor immunosuppressive environment possibly induced by chemotherapy‐mediated tumor‐intrinsic programmed death‐ligand 1 (PD‐L1) upregulation or tumor‐associated macrophages (TAMs) promoting additional PD‐L1 expression on tumor cells through distinct paracrine signaling pathways. To overcome this dual resistance mechanism, we developed a hyaluronic acid‐functionalized nanoplatform for co‐delivering DOX and nitric oxide (NO) donor S‐nitroso‐N‐acetylpenicillamine (SNAP), termed HA‐DS@PLGA. This system facilitates dual targeting of CD44‐overexpressing tumor cells and TAMs via HA‐mediated recognition while the PLGA core ensures sustained release of both agents. SNAP‐derived NO effectively attenuates DOX‐induced PD‐L1 expression through NO‐mediated signaling disruption while synergistically potentiating DOX's immunogenic cell death effects. In TAMs, the system synergistically eliminates M2 macrophages and reprograms residual macrophages toward the tumoricidal M1 phenotype via PI3K‐AKT signaling. In 4T1‐tumor‐bearing mouse models, HA‐DS@PLGA achieved 95.8%, 94.5%, and 88.4% tumor inhibition versus PBS, HA‐S@PLGA (SNAP alone), and HA‐D@PLGA (DOX alone), respectively. Meanwhile, HA‐DS@PLGA elicited systemic immunity, as evidenced by enhanced dendritic cell maturation, increased cytotoxic T lymphocyte infiltration, elevated IFN‐γ production, and downregulation of PD‐L1. By simultaneously targeting tumor‐intrinsic and microenvironment‐mediated immunosuppression, HA‐DS@PLGA overcomes multifaceted resistance mechanisms and amplifies antitumor immunity, offering a promising paradigm for combinatorial cancer nanomedicine.