Multifunctional copper complex-mediated self-blocking plasmid delivery of PD-L1 for tumor chemoimmunotherapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Immunotherapy

Background:

• Copper-based therapies show promise in cancer treatment by inducing immunogenic cell death and synergizing with PD-1/PD-L1 blockade.
• Challenges include adaptive DNA damage repair and inefficient tumor-specific delivery, limiting therapeutic efficacy.

Purpose of the Study:

• To develop a biomimetic nanoplatform for targeted co-delivery of copper ions, Olaparib, and PD-L1 trap plasmids.
• To enhance antitumor immune responses by overcoming drug resistance and improving tumor microenvironment modulation.

Main Methods:

• Constructed a nanoparticle framework using polyethyleneimine (PEI) and Olaparib (Ola), incorporating Cu²⁺ and pPD-L1 trap plasmid.
• Camouflaged the nanoparticles with homologous tumor cell membranes and conjugated R15 peptides for nuclear targeting.
• Investigated the synergistic effects of Cu²⁺, Ola, and PD-L1 trap in vitro and in vivo.

Main Results:

• The nanoplatform demonstrated prolonged blood circulation and efficient tumor-targeted delivery.
• Intracellular Cu²⁺ and Ola induced Fenton-like reactions and DNA damage, enhancing tumor immunogenicity.
• The system effectively remodeled the immunosuppressive tumor microenvironment and amplified antitumor immunity.

Conclusions:

• The developed biomimetic drug delivery system achieved targeted co-delivery of multiple therapeutic agents.
• This strategy shows significant potential for combined chemotherapy and immunotherapy against tumors.
• The platform offers a promising approach to enhance synergistic antitumor effects and overcome therapeutic limitations.