Prodrug-Doped ROS-Responsive Lipid Nanoparticle for Enhanced mRNA Delivery and Synergistic Anti-Tumor Therapy

Area of Science:

• Biotechnology
• Nanomedicine
• Cancer Therapeutics

Background:

• Lipid nanoparticles (LNPs) are advanced mRNA delivery platforms for cancer therapeutics.
• Conventional LNP-mRNA systems face challenges in endosomal release and synergistic therapy integration.

Purpose of the Study:

• To develop a reactive oxygen species (ROS)-responsive prodrug-doped LNP (LNP-Pro) for enhanced mRNA delivery and synergistic anti-tumor therapy.
• To overcome limitations of conventional LNP-mRNA systems.

Main Methods:

• Incorporation of a camptothecin (CPT)-based prodrug, linked via a ROS-cleavable bond, into clinically approved LNP formulations.
• Evaluation of LNP-Pro's response to tumor cell ROS microenvironment and its delivery capacity.
• In vitro and in vivo studies to assess mRNA delivery efficacy and therapeutic synergy.

Main Results:

• LNP-Pro demonstrated superior delivery in tumor cells due to ROS responsiveness.
• Significantly enhanced mRNA delivery efficacy compared to conventional LNPs.
• Synergistic anti-tumor effect of mRNA and CPT chemotherapeutic, leading to significant tumor growth inhibition in a murine model.
• Excellent biocompatibility of the LNP-Pro system.

Conclusions:

• The developed LNP-Pro system provides a versatile platform for mRNA-based cancer therapy.
• Integration of stimulus-responsive prodrugs with LNPs enhances therapeutic efficacy.
• This strategy offers a promising approach for synergistic anti-tumor treatment.