Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing

Piul S. Rabbani, Anna Zhou, Zachary M. Borab, Joseph A. Frezzo, Nikita Srivastava, Haresh T. More, William J. Rifkin, Joshua A. David, Samuel J. Berens, Raymond Chen, Sophia Hameedi, Muhammad H. Junejo, Camille Kim, Rita A. Sartor, Che F. Liu, Pierre B. Saadeh, Jin Montclare, Daniel J. Ceradini

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1-15
Number of pages15
JournalBiomaterials
Volume132
DOIs
StatePublished - Jul 1 2017

Fingerprint

Gene therapy
Genetic Therapy
Wound Healing
Small Interfering RNA
Nanoparticles
Propane
Proteins
Tissue regeneration
Oxidative stress
Skin Diseases
Liposomes
Cytotoxicity
Antioxidants
Complexation
Wounds and Injuries
Lipids
Sodium Cholate
Skin
Sodium
Availability

Keywords

  • Diabetic wound
  • Gene therapy
  • Keap1
  • Lipoproteoplex vehicle
  • Nrf2
  • siRNA

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

Rabbani, P. S., Zhou, A., Borab, Z. M., Frezzo, J. A., Srivastava, N., More, H. T., ... Ceradini, D. J. (2017). Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing. Biomaterials, 132, 1-15. https://doi.org/10.1016/j.biomaterials.2017.04.001

Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing. / Rabbani, Piul S.; Zhou, Anna; Borab, Zachary M.; Frezzo, Joseph A.; Srivastava, Nikita; More, Haresh T.; Rifkin, William J.; David, Joshua A.; Berens, Samuel J.; Chen, Raymond; Hameedi, Sophia; Junejo, Muhammad H.; Kim, Camille; Sartor, Rita A.; Liu, Che F.; Saadeh, Pierre B.; Montclare, Jin; Ceradini, Daniel J.

In: Biomaterials, Vol. 132, 01.07.2017, p. 1-15.

Research output: Contribution to journalArticle

Rabbani, PS, Zhou, A, Borab, ZM, Frezzo, JA, Srivastava, N, More, HT, Rifkin, WJ, David, JA, Berens, SJ, Chen, R, Hameedi, S, Junejo, MH, Kim, C, Sartor, RA, Liu, CF, Saadeh, PB, Montclare, J & Ceradini, DJ 2017, 'Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing', Biomaterials, vol. 132, pp. 1-15. https://doi.org/10.1016/j.biomaterials.2017.04.001
Rabbani, Piul S. ; Zhou, Anna ; Borab, Zachary M. ; Frezzo, Joseph A. ; Srivastava, Nikita ; More, Haresh T. ; Rifkin, William J. ; David, Joshua A. ; Berens, Samuel J. ; Chen, Raymond ; Hameedi, Sophia ; Junejo, Muhammad H. ; Kim, Camille ; Sartor, Rita A. ; Liu, Che F. ; Saadeh, Pierre B. ; Montclare, Jin ; Ceradini, Daniel J. / Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing. In: Biomaterials. 2017 ; Vol. 132. pp. 1-15.
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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.",
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AU - Srivastava, Nikita

AU - More, Haresh T.

AU - Rifkin, William J.

AU - David, Joshua A.

AU - Berens, Samuel J.

AU - Chen, Raymond

AU - Hameedi, Sophia

AU - Junejo, Muhammad H.

AU - Kim, Camille

AU - Sartor, Rita A.

AU - Liu, Che F.

AU - Saadeh, Pierre B.

AU - Montclare, Jin

AU - Ceradini, Daniel J.

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