Biomimetic PD-1 macrophage nanoplatform for Cip2a silencing and immune activation in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) remains a highly aggressive malignancy in which immune checkpoint blockade alone shows limited efficacy due to persistent tumor-intrinsic survival signaling and an immunosuppressive tumor microenvironment. Here, we report a biomimetic nanoplatform, siCip2a@PML, designed to integrate tumor-intrinsic apoptosis induction with immune checkpoint blockade. Cancerous inhibitor of protein phosphatase 2A (Cip2a) siRNA (siCip2a) is encapsulated within lipid nanoparticles to suppress OSCC cell growth through apoptosis induction, while the nanoparticles are cloaked with PD-1-overexpressing macrophage membrane to enable tumor targeting and competitive blockade of PD-1/PD-L1 signaling. The rationale for this combinatorial strategy is supported by clinical specimen analysis and The Cancer Genome Atlas (TCGA) data, which reveal elevated expression of Cip2a and PD-L1 in OSCC and their association with poor prognosis. siCip2a@PML exhibits enhanced tumor accumulation, efficient gene silencing, and potent antitumor activity in vitro and in vivo. Importantly, PD-1-functionalized membrane camouflage promotes dendritic cells maturation, increases intratumoral infiltration of CD4⁺ and CD8⁺ T cells, and restores antitumor immune responses. By uniting tumor-intrinsic growth suppression with immune checkpoint modulation in a single delivery system, this work presents a clinically informed gene-immunotherapy strategy and offers a promising therapeutic paradigm for OSCC.