Targeted, Enhanced Modification Of Lipid NanoparticlesTto Improve Tumor Therapeutic Efficacy

A method to inhibit small extracellular vesicles (sEVs) released by tumor cells to enhance lipid nanoparticle (LNP) accumulation in tumors.
Problem:
Lipid nanoparticles (LNPs) have shown promise as drug delivery systems for various diseases with several clinically approved products. However, their ability to deliver genes specifically to tumor cells has been limited and challenging. This results in reduced nanoparticle penetration and accumulation within tumors, ultimately lowering the treatment’s effectiveness. Therefore, there is a need to improve delivery efficiency to enhance the treatment outcome.
Solution:
The inventors found that sEVs from tumor cells function as barriers by binding to LNPs and directing them to the liver, reducing tumor accumulation. Inhibiting the Rab27a gene, which controls sEV secretion, enhances nanoparticle delivery. Co-delivering LNPs with small interfering RNA (siRNA) targeting Rab27a decreases sEV levels, resulting in improved nanoparticle delivery to the tumor cells.
Technology:
The inventors used CRISPR-Cas9 to induce Rab27a knockout (KO) in mouse colon and melanoma tumor cell lines. In wild-type (WT) mice, LNPs primarily accumulated in the liver and spleen, while Rab27a KO mice showed significant LNP distribution within tumors, indicating improved nanoparticle uptake by tumor cells. They found that LNPs bind to sEVs, forming a complex that Kupffer cells in the liver capture via ICAM-1 and Mac-1 interactions, leading to degradation. This defense system has broader therapeutic implications since the sEV defense system also affects other nanoparticle-based therapeutics, such as viral and antibody treatments.
Advantages:

Inhibition of sEV secretion by Rab27a KO increased LNP uptake by cells in tumors and simultaneously decreased uptake by Kupffer cells
siRab27a-LNP pre-treatment substantially improved spheroid penetration
sEV-based defense system may influence other nanoparticle-based therapies in the clinic

Stage of Development:

Proof of Concept

(A) This figure describes how the presence of small Extracellular Vesicles released by the tumor cells function as a barrier for nanoparticles from penetrating and accumulating in the tumor cells. sEVs bind to the nanoparticles and are taken to the liver cells for degradation. (B) The plot describes the quantification of the mean fluorescence intensity (MFI) signal in the liver. It can be observed that the signal is lower in the KO mice than the WT mice. (C) This plot describes the MFI in the tumor cells and the signal is higher in KO mice than the WT mice.
Intellectual Property: