A Nanobody-LNP Platform for Targeting and Relicensing Dendritic Cells for Potent Cancer Immunotherapy

Area of Science:

• Immunology
• Nanotechnology
• Oncology

Background:

• Cancer immunotherapy faces challenges in antigen delivery to dendritic cells (DCs) and overcoming local immunosuppression.
• Developing strategies to enhance DC function is crucial for effective anti-tumor immunity.

Purpose of the Study:

• To develop a dual-action nanobody-lipid nanoparticle (LNP) platform for enhanced cancer immunotherapy.
• To target DCs via the Plastin-2 (PLS2) receptor and simultaneously modulate DC function.

Main Methods:

• Lipid nanoparticles were decorated with nanobodies targeting the DC surface protein Plastin-2 (PLS2).
• The platform was evaluated for DC internalization efficiency, antigen expression, and DC phenotype modulation.
• Inhibition of the Leptin-JAK2-STAT3 signaling pathway was assessed.
• The platform's efficacy in eliciting cytotoxic T lymphocyte (CTL) responses and inhibiting established tumors was investigated.

Main Results:

• The nanobody-LNP platform achieved 93% DC internalization efficiency.
• Targeted delivery enhanced antigen expression and relicensed DCs to a mature, potent phenotype.
• The platform inhibited the immunosuppressive Leptin-JAK2-STAT3 pathway.
• Significant CTL responses and marked inhibition of established tumors were observed.

Conclusions:

• Plastin-2 (PLS2) is identified as a novel immunomodulatory receptor on DCs.
• The nanobody-LNP platform offers a dual-action strategy for boosting cancer vaccine potency.
• This approach shows significant promise for improving cancer immunotherapy outcomes.