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Endogenous Targeting of Lipid Nanoparticles to Kidney Tumors
Amogh Vaidya1,2, Yun-Chieh Sung1,2, Vanina Toffessi Tcheuyap3,4
1Department of Biomedical Engineering, Program in Genetic Drug Engineering, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
Abstract:
Although the delivery of genetic therapies to tumors using nanoparticles remains challenging, targeting may be enabled via plasma membrane receptors overexpressed on certain cancer cells. Here, we developed an endogenous targeting strategy for trafficking intravenously administered mRNA (and siRNA) lipid nanoparticles (LNPs) to clear cell renal cell carcinoma (ccRCC) kidney tumors. LNPs were engineered to adsorb circulating plasma vitronectin (Vtn), the ligand for αVβ3 integrin/vitronectin receptor (Vtn-R), which is overexpressed in ccRCC. Functional mRNA delivery to human ccRCC cells was enhanced 952-fold in vitro and 42-fold in patient-derived ccRCC tumor fragments orthotopically transplanted in mice. This proof-of-concept study represents a new direction in the cancer nanomedicine field by modulating the physicochemical properties of LNPs to achieve in situ ligand binding and tumor targeting.
Insights
Researchers engineered lipid nanoparticles (LNPs) to target kidney cancer by binding to vitronectin, a protein overexpressed in clear cell renal cell carcinoma (ccRCC). This strategy significantly enhanced mRNA delivery to ccRCC tumors both in vitro and in vivo.
Area of Science:
- Biomedical Engineering
- Nanomedicine
- Oncology
Background:
- Targeting tumors with nanomedicines, particularly lipid nanoparticles (LNPs) for genetic therapies, faces significant challenges.
- Plasma membrane receptors overexpressed on cancer cells offer potential targets for nanoparticle delivery.
- Clear cell renal cell carcinoma (ccRCC) exhibits overexpression of specific receptors, presenting an opportunity for targeted therapy.
Purpose of the Study:
- To develop an endogenous targeting strategy for delivering mRNA and siRNA using lipid nanoparticles (LNPs) to clear cell renal cell carcinoma (ccRCC) tumors.
- To engineer LNPs that can adsorb circulating plasma vitronectin (Vtn) for targeting the αVβ3 integrin/vitronectin receptor (Vtn-R) complex overexpressed in ccRCC.
Main Methods:
- Engineered lipid nanoparticles (LNPs) to adsorb circulating plasma vitronectin (Vtn).
- Utilized the Vtn-Vtn-R binding interaction for targeting ccRCC tumors.
- Assessed functional mRNA delivery efficiency in vitro to human ccRCC cells and in vivo using patient-derived ccRCC tumor fragments in mice.
Main Results:
- Engineered LNPs demonstrated enhanced mRNA delivery to ccRCC cells in vitro, with a 952-fold increase.
- In vivo studies showed a 42-fold enhancement in mRNA delivery to orthotopically transplanted ccRCC tumor fragments.
- The strategy leverages endogenous ligands and receptor interactions for tumor-specific targeting.
Conclusions:
- This study presents a novel endogenous targeting strategy for nanoparticle-based cancer therapies.
- Modulating LNP physicochemical properties for in situ ligand binding enables effective tumor targeting.
- This approach offers a promising new direction for nanomedicine in treating ccRCC and potentially other cancers.
