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. 2025 Sep 2;19(34):30860-30871.
doi: 10.1021/acsnano.5c05370. Epub 2025 Aug 20.

Endogenous Targeting of Lipid Nanoparticles to Kidney Tumors

Amogh Vaidya  1   2 , Yun-Chieh Sung  1   2 , Vanina Toffessi Tcheuyap  3   4 , Chengcheng Zhang  3   4 , Ramesh Butti  3   4 , Arijit Mal  3   4 , Sean Dilliard  1   2 , Jing Liu  1   2 , Eunice Song  1   2 , Erick Guerrero  1   2 , Priyanka Patel  1   2 , Julien Santelli  1   2 , Jeffrey Miyata  3   4 , Stephen Moore  1   2 , Sumanta Chatterjee  1   2 , Gopinath Prakasam  3   4 , Yufen Xiao  1   2 , Payal Kapur  4   5 , James Brugarolas  3   4 , Daniel J Siegwart  1   2
Affiliations

Endogenous Targeting of Lipid Nanoparticles to Kidney Tumors

Amogh Vaidya et al. ACS Nano. .

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.

Keywords: HIF2α; RCC; endogenous targeting; kidney cancer; lipid nanoparticles; mRNA; siRNA.

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