Engineered extracellular vesicles for combinatorial TNBC therapy: SR-SIM-guided design achieves substantial drug dosage reduction.

Autor:	Bhullar AS; Center for RNA Nanobiotechnology and Nanomedicine, College of Pharmacy and Comprehensive Cancer Center. The Ohio State University, Columbus, OH 43210, USA; Interdisciplinary Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210, USA., Jin K; Center for RNA Nanobiotechnology and Nanomedicine, College of Pharmacy and Comprehensive Cancer Center. The Ohio State University, Columbus, OH 43210, USA., Shi H; Markey Cancer Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA., Jones A; Department of Veterinary Biosciences, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA., Hironaka D; Department of Veterinary Biosciences, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA., Xiong G; Department of Veterinary Biosciences, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA., Xu R; Markey Cancer Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA., Guo P; Center for RNA Nanobiotechnology and Nanomedicine, College of Pharmacy and Comprehensive Cancer Center. The Ohio State University, Columbus, OH 43210, USA; Interdisciplinary Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210, USA., Binzel DW; Center for RNA Nanobiotechnology and Nanomedicine, College of Pharmacy and Comprehensive Cancer Center. The Ohio State University, Columbus, OH 43210, USA. Electronic address: binzel.2@osu.edu., Shu D; Center for RNA Nanobiotechnology and Nanomedicine, College of Pharmacy and Comprehensive Cancer Center. The Ohio State University, Columbus, OH 43210, USA. Electronic address: shu.135@osu.edu.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Dec 04; Vol. 32 (12), pp. 4467-4481. Date of Electronic Publication: 2024 Oct 05.
DOI:	10.1016/j.ymthe.2024.09.034
Abstrakt:	Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that has no therapeutic targets, relies on chemotherapeutics for treatment, and is in dire need of novel therapeutic approaches for improved patient outcomes. Extracellular vesicles (EVs) serve as intercellular communicators and have been proposed as ideal drug delivery vehicles. Here, EVs were engineered with RNA nanotechnology to develop TNBC tumor inhibitors. Using super resolved-structured illumination microscopy, EVs were optimized for precise Survivin small interfering RNA (siRNA) conjugated to chemotherapeutics loading and CD44 aptamer ligand decoration, thereby enhancing specificity toward TNBC cells. Conventional treatments typically employ chemotherapy drugs gemcitabine (GEM) and paclitaxel (PTX) at dosages on the order of mg/kg respectively, per injection (intravenous) in mice. In contrast, engineered EVs encapsulating these drugs saw functional tumor growth inhibition at significantly reduced concentrations: 2.2 μg/kg for GEM or 5.6 μg/kg for PTX, in combination with 21.5 μg/kg survivin-siRNA in mice. The result is a substantial decrease in the chemotherapeutic dose required, by orders of magnitude, compared with standard regimens. In vivo and in vitro evaluations in a TNBC orthotopic xenograft mouse model demonstrated the efficacy of this decreased dosage strategy, indicating the potential for decreased chemotherapy-associated toxicity. Competing Interests: Declaration of interests P.G.’s Sylvan Frank Endowed Chair in Pharmaceutics and Drug Delivery position is supported by the Chen’s Foundation. P.G. is the consultant, licensor, and grantee of Oxford Nanopore Technologies. P.G. also has a patent EP3440090B1 RNA ligand-displaying exosomes for specific delivery of therapeutics to cell by RNA nanotechnology. (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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