title: Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing.
abstract: Therapeutics utilizing siRNA are currently limited by the availability of safe and effective delivery systems. Cutaneous diseases, specifically ones with significant genetic components are ideal candidates for topical siRNA based therapy but the anatomical structure of skin presents a considerable hurdle. Here, we optimized a novel liposome and protein hybrid nanoparticle delivery system for the topical treatment of diabetic wounds with severe oxidative stress. We utilized a cationic lipid nanoparticle (CLN) composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the edge activator sodium cholate (NaChol), in a 6:1 ratio of DOTAP:NaChol (DNC). Addition of a cationic engineered supercharged coiled-coil protein (CSP) in a 10:1:1 ratio of DNC:CSP:siRNA produced a stable lipoproteoplex (LPP) nanoparticle, with optimal siRNA complexation, minimal cytotoxicity, and increased transfection efficacy. In a humanized murine diabetic wound healing model, our optimized LPP formulation successfully delivered siRNA targeted against Keap1, key repressor of Nrf2 which is a central regulator of redox mechanisms. Application of LPP complexing siKeap1 restored Nrf2 antioxidant function, accelerated diabetic tissue regeneration, and augmented reduction-oxidation homeostasis in the wound environment. Our topical LPP delivery system can readily be translated into clinical use for the treatment of diabetic wounds and can be extended to other cutaneous diseases with genetic components.
authors.affiliation: New York University School of Medicine, Hansjörg Wyss Department of Plastic and Reconstructive Surgery, 430 East 29th Street, New York, NY, 10016, United States.
authors.forename: Piul S
authors.initials: PS
authors.lastname: Rabbani
authors.affiliation: New York University School of Medicine, Hansjörg Wyss Department of Plastic and Reconstructive Surgery, 430 East 29th Street, New York, NY, 10016, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Zhou
authors.affiliation: New York University School of Medicine, Hansjörg Wyss Department of Plastic and Reconstructive Surgery, 430 East 29th Street, New York, NY, 10016, United States.
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: Borab
authors.affiliation: New York University Tandon School of Engineering, Chemical and Biomolecular Engineering Department, 6 Metrotech Center, Brooklyn, NY 11201, United States.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Frezzo
authors.affiliation: New York University Tandon School of Engineering, Chemical and Biomolecular Engineering Department, 6 Metrotech Center, Brooklyn, NY 11201, United States.
authors.forename: Nikita
authors.initials: N
authors.lastname: Srivastava
authors.affiliation: New York University Tandon School of Engineering, Chemical and Biomolecular Engineering Department, 6 Metrotech Center, Brooklyn, NY 11201, United States.
authors.forename: Haresh T
authors.initials: HT
authors.lastname: More
authors.affiliation: New York University School of Medicine, Hansjörg Wyss Department of Plastic and Reconstructive Surgery, 430 East 29th Street, New York, NY, 10016, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Rifkin
authors.affiliation: New York University School of Medicine, Hansjörg Wyss Department of Plastic and Reconstructive Surgery, 430 East 29th Street, New York, NY, 10016, United States.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: David
authors.affiliation: New York University Tandon School of Engineering, Chemical and Biomolecular Engineering Department, 6 Metrotech Center, Brooklyn, NY 11201, United States.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Berens
authors.affiliation: New York University Tandon School of Engineering, Chemical and Biomolecular Engineering Department, 6 Metrotech Center, Brooklyn, NY 11201, United States.
authors.forename: Raymond
authors.initials: R
authors.lastname: Chen
authors.affiliation: New York University School of Medicine, Hansjörg Wyss Department of Plastic and Reconstructive Surgery, 430 East 29th Street, New York, NY, 10016, United States.
authors.forename: Sophia
authors.initials: S
authors.lastname: Hameedi
authors.affiliation: New York University School of Medicine, Hansjörg Wyss Department of Plastic and Reconstructive Surgery, 430 East 29th Street, New York, NY, 10016, United States.
authors.forename: Muhammad H
authors.initials: MH
authors.lastname: Junejo
authors.affiliation: New York University School of Medicine, Hansjörg Wyss Department of Plastic and Reconstructive Surgery, 430 East 29th Street, New York, NY, 10016, United States.
authors.forename: Camille
authors.initials: C
authors.lastname: Kim
authors.affiliation: New York University School of Medicine, Hansjörg Wyss Department of Plastic and Reconstructive Surgery, 430 East 29th Street, New York, NY, 10016, United States.
authors.forename: Rita A
authors.initials: RA
authors.lastname: Sartor
authors.affiliation: New York University Tandon School of Engineering, Chemical and Biomolecular Engineering Department, 6 Metrotech Center, Brooklyn, NY 11201, United States.
authors.forename: Che F
authors.initials: CF
authors.lastname: Liu
authors.affiliation: New York University School of Medicine, Hansjörg Wyss Department of Plastic and Reconstructive Surgery, 430 East 29th Street, New York, NY, 10016, United States.
authors.forename: Pierre B
authors.initials: PB
authors.lastname: Saadeh
authors.affiliation: New York University Tandon School of Engineering, Chemical and Biomolecular Engineering Department, 6 Metrotech Center, Brooklyn, NY 11201, United States; New York University, Chemistry Department, 100 Washington Square East, New York, NY 10003, United States.
authors.forename: Jin K
authors.initials: JK
authors.lastname: Montclare
authors.affiliation: New York University School of Medicine, Hansjörg Wyss Department of Plastic and Reconstructive Surgery, 430 East 29th Street, New York, NY, 10016, United States. Electronic address: Daniel.Ceradini@nyumc.org.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Ceradini
mesh_terms: D000287:Administration, Topical; D000818:Animals; D002470:Cell Survival; D048909:Diabetes Complications / Q000209:etiology / Q000235:genetics / Q000628:therapy*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000628:therapy*; D020868:Gene Silencing; D015316:Genetic Therapy; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics*; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D053758:Nanoparticles; D010316:Particle Size; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D012867:Skin / Q000473:pathology; D014162:Transfection; D014945:Wound Healing
chemical_list: D000072019:Kelch-Like ECH-Associated Protein 1; D008055:Lipids; D008081:Liposomes; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D034741:RNA, Small Interfering
keywords: Diabetic wound; Gene therapy; Keap1; Lipoproteoplex vehicle; Nrf2; siRNA