Ionizable lipid nanoparticles for RAS protease delivery to inhibit cancer cell proliferation

Area of Science:

• Biotechnology
• Oncology
• Nanomedicine

Background:

• RAS protein mutations drive approximately one-third of all human cancers.
• Effective clinical therapies targeting oncogenic RAS proteins remain limited.
• Intracellular protein-based therapies require efficient delivery systems.

Purpose of the Study:

• To develop and evaluate ionizable lipid nanoparticles (LNPs) as a delivery platform for RAS proteases.
• To assess the efficacy of LNP-delivered RAS proteases in inhibiting cancer cell proliferation in vitro and in vivo.
• To optimize LNP formulations for enhanced delivery, biodistribution, and reduced toxicity.

Main Methods:

• Designed and synthesized a library of 13 cationic lipid-containing LNPs encapsulating RAS protease.
• Evaluated LNP formulations for in vitro delivery efficiency and cytotoxicity.
• Assessed the anti-proliferative effects of top-performing LNP formulations in KRAS-mutated colorectal cancer cells.
• Conducted in vivo studies using a xenograft model to evaluate LNP biodistribution, tumor growth inhibition, and toxicity.

Main Results:

• Identified four top-performing LNP formulations with efficient in vitro delivery and RAS protease functionality.
• Demonstrated that both cationic lipid concentration and cargo type influenced in vivo LNP and cargo distribution.
• Showcased significant reduction in cancer cell proliferation and tumor growth in vivo with the lead LNP formulation.
• Confirmed effective intracellular delivery of RAS protease in vivo.

Conclusions:

• Ionizable lipid nanoparticles serve as a viable and effective delivery platform for intracellular RAS proteases.
• This LNP-based approach holds potential for the development of novel cancer therapeutics targeting RAS-driven tumors.
• Further development of this platform could lead to new treatment strategies for various cancers, including colorectal, pancreatic, and lung cancers.