A novel pH-sensitive nanoparticles encapsulating anti-PD-1 antibody and MDK-siRNA overcome immune checkpoint blockade resistance in HCC via reshaping immunosuppressive TME

Abstract

Abstract Objective Immunotherapy, notably the immune checkpoint blockade (ICB), has demonstrated significant promise in the management of diverse neoplasms. However, the PD-1 inhibitor has exhibited suboptimal objective response rates and did not achieve the primary endpoints in hepatocellular carcinoma (HCC) patients, primarily due to resistance to ICB fostered by the immunosuppressive tumor microenvironment (TME). To address ICI resistance and minimize adverse effects, we have engineered an innovative tumor-specific nanomedicine for the concurrent administration of aPD-1 and MDK-siRNA. Methods Both in vitro and orthotopic HCC models were employed to investigate and establish the efficacy of the novel tumor-specific nanomedicine in overcoming the immunosuppressive TME. Specifically, the impact of the nanomedicine on the M2 polarization and polyamine metabolism within tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) was delineated. The immunomodulatory and antitumor effects, along with the side effects, of the nanomedicine integrating both aPD-1 and MDK-siRNA were assessed. Results A dual pH-responsive nanomedicine was successfully fabricated to co-deliver MDK-siRNA and aPD-1. The nanomedicine achieved targeted drug delivery to tumors by engaging with circulating PD-1+ T cells and accompanying their migration into the tumor mass. Additionally, nanomedicine promoted efficient drug release within the acidic TME, deploying aPD-1 for ICI therapy and retaining MDK-siRNA-encapsulated nanomedicine to regulate TAMs and MDSCs synergistically. The synergistic application of MDK-siRNA and aPD-1, coupled with the efficient tumor-targeted drug delivery, potently suppressed M2 polarization and polyamine metabolism in TAMs and MDSCs, thereby overcoming the immunosuppressive TME and leading to significant therapeutic efficacy with minimal side effects in HCC. Conclusion We have developed an innovative tumor-specific nanocarrier for the co-delivery of aPD-1 and MDK-siRNA. We validated that the synthesized nanomedicine (aPD-1-siRNA@NP) yielded highly effective treatment and minimal side effects in both in vitro and orthotopic HCC models. Our work presents a nanomedicine-based approach for targeted dual-drug delivery, achieving notable efficacy in the treatment of HCC.

Keywords

• Hepatocellular carcinoma
• Nanodrug
• Midkine
• Tumor-associated macrophages
• Myeloid-derived suppressor cells
• Immunotherapy