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

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.