Functionalized Biomimetic Carrier-Free Metal-Coordinated Nanoplatform for Multidimensional Synergistic Therapy of Breast Cancer

Despite the increasing clinical application of combination therapy, assembling metal ions, nucleic acid therapeutics, and small-molecule chemotherapeutic agents into a single carrier-free nanoparticle remains a significant technical challenge. In this study, a three-component self-assembly was successfully achieved through synergistic π-π stacking and electrostatic interactions among copper ions (Cu²⁺), small interfering RNA targeting PD-L1 (siPD-L1), and doxorubicin (DOX), leading to the formation of stable therapeutic nanoparticles (siPD-L1/DOX/Cu NPs). The obtained NPs were subsequently camouflaged with red blood cell membranes (RBCm), a modification that significantly enhanced the colloidal stability, dispersibility, and systemic circulation time. The siPD-L1/DOX/Cu@RBCm NPs exhibited pronounced chemodynamic therapeutic effects and GSH-responsive drug release behavior. In the high-level GSH environment of tumor cells, Cu²⁺ could deplete intracellular GSH and trigger chemodynamic therapy, while DOX induced oxidative stress, synergistically activating the apoptotic pathway. The released siPD-L1 effectively silenced PD-L1 expression, thereby alleviating the immunosuppressive tumor microenvironment, while synergistically augmenting immunotherapeutic outcomes. Compared with uncoated nanoparticles, siPD-L1/DOX/Cu@RBCm NPs demonstrated a longer blood circulation half-life and higher tumor-targeted accumulation <i>in vivo</i>. In animal models, these engineered NPs markedly suppressed tumor progression, while showing no detectable systemic side effects. This multifunctional nanoplatform therefore presents an integrated therapeutic strategy that synergizes chemotherapy, immunotherapy, and chemodynamic therapy. This approach provides an innovative design guide for cancer treatment.