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Biomimetic PD-1 macrophage nanoplatform for Cip2a silencing and immune activation in oral squamous cell carcinoma
Chenyu Zhang1,2, Zhe Yuan1, Jie Zhou1
1Department of Oral and Maxillofacial Surgery, School of Stomatology, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, P. R. China.
Abstract:
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.
Insights
This study introduces a novel nanoplatform for oral cancer, combining gene therapy to induce apoptosis with immunotherapy to block immune checkpoints. This dual approach shows potent antitumor activity and enhances immune responses against OSCC.
Area of Science:
- Biomedical Engineering
- Cancer Immunology
- Nanomedicine
Background:
- Oral squamous cell carcinoma (OSCC) is aggressive, with limited response to current immunotherapies due to tumor survival signals and immunosuppression.
- Existing treatments struggle with tumor-intrinsic resistance and a hostile microenvironment.
Purpose of the Study:
- To develop a biomimetic nanoplatform (siCip2a@PML) integrating apoptosis induction and immune checkpoint blockade for OSCC treatment.
- To investigate the efficacy of targeting Cancerous inhibitor of protein phosphatase 2A (Cip2a) and PD-1/PD-L1 signaling simultaneously.
Main Methods:
- siCip2a encapsulated in lipid nanoparticles for apoptosis induction, cloaked with PD-1-overexpressing macrophage membranes for tumor targeting and PD-1/PD-L1 blockade.
- Utilized clinical OSCC specimens and TCGA data to validate targets Cip2a and PD-L1.
- Evaluated nanoplatform performance in vitro and in vivo for tumor accumulation, gene silencing, and antitumor effects.
Main Results:
- siCip2a@PML demonstrated enhanced tumor targeting, efficient gene silencing, and significant antitumor activity.
- The nanoplatform promoted dendritic cell maturation and increased CD4+/CD8+ T cell infiltration into tumors.
- Restored antitumor immune responses were observed, indicating successful immune modulation.
Conclusions:
- The siCip2a@PML nanoplatform offers a promising combinatorial gene-immunotherapy strategy for OSCC.
- This approach effectively combines tumor-intrinsic apoptosis induction with immune checkpoint modulation for enhanced therapeutic outcomes.
