Skin-targeted delivery of extracellular vesicle-encapsulated curcumin using dissolvable microneedle arrays

Saigopalakrishna S Yerneni; Ezgi P Yalcintas; Jason D Smith; Saadyah Averick; Phil G Campbell; O Burak Ozdoganlar

doi:10.1016/j.actbio.2022.06.046

Skin-targeted delivery of extracellular vesicle-encapsulated curcumin using dissolvable microneedle arrays

Acta Biomater. 2022 Sep 1:149:198-212. doi: 10.1016/j.actbio.2022.06.046. Epub 2022 Jul 6.

Authors

Saigopalakrishna S Yerneni¹, Ezgi P Yalcintas², Jason D Smith³, Saadyah Averick⁴, Phil G Campbell⁵, O Burak Ozdoganlar⁶

Affiliations

¹ Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
² Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
³ Engineering Research Accelerator, Carnegie Mellon University, Pittsburgh, PA, USA.
⁴ Neuroscience Institute, Allegheny Health Network, Allegheny General Hospital, Pittsburgh, PA, USA.; Neuroscience Disruptive Research Lab, Allegheny General Hospital, Pittsburgh, PA, USA.
⁵ Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA; Engineering Research Accelerator, Carnegie Mellon University, Pittsburgh, PA, USA. Electronic address: pcampbel@cs.cmu.edu.
⁶ Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA; Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA; Department of Material Science and Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. Electronic address: ozdoganlar@cmu.edu.

PMID: 35809788
DOI: 10.1016/j.actbio.2022.06.046

Abstract

Therapeutic benefits of curcumin for inflammatory diseases have been demonstrated. However, curcumin's potential as a clinical therapeutic has been hindered due to its low solubility and stability in vivo. We hypothesized that a hybrid curcumin carrier that incorporates albumin-binding and extracellular vesicle (EV) encapsulation could effectively address the current challenges of curcumin delivery. We further postulated that using dissolvable microneedle arrays (dMNAs) for local delivery of curcumin-albumin-EVs (CA-EVs) could effectively control skin inflammation in vivo. Mild sonication was used to encapsulate curcumin and albumin into EVs, and the resulting CA-EVs were integrated into tip-loaded dMNAs. In vitro and in vivo studies were performed to assess the stability, cellular uptake, and anti-inflammatory bioactivity of dMNA-delivered CA-EVs. Curcumin in CA-EVs exhibited at least five-fold higher stability in vitro than naïve curcumin or curcumin-EVs without albumin. Incorporating CA-EVs into dMNAs did not alter their cellular uptake or anti-inflammatory bioactivity. The dMNA embedded CA-EVs retained their bioactivity when stored at room temperature for at least 12 months. In rat and mice models, dMNA delivered CA-EVs suppressed and significantly reduced lipopolysaccharide and Imiquimod-triggered inflammation. We conclude that dMNA delivery of CA-EVs has the potential to become an effective local-delivery strategy for inflammatory skin diseases. STATEMENT OF SIGNIFICANCE: We introduce and evaluate a skin-targeted delivery system for curcumin that synergistically combines albumin association, extracellular-vesicle encapsulation, and dissolvable microneedle arrays (dMNAs) . In vitro, curcumin-albumin encapsulated extracellular vesicles (CA-EVs) inhibit and reverse the LPS-triggered expression of inflammatory transcription factor NF-κB. The integration of CA-EVs into dMNAs does not affect them physically or functionally. Importantly, dMNAs extend EV storage stability for at least 12 months at room temperature with minimal loss in their bioactivity. We demonstrate that dMNA delivered CA-EVs effectively block and reverse skin inflammation in vivo in mouse and rat models.

Keywords: Curcumin; Drug delivery; Exosomes; Extracellular vesicles; Inflammation; Microneedle arrays.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Albumins / pharmacology
Animals
Anti-Inflammatory Agents / pharmacology
Anti-Inflammatory Agents / therapeutic use
Curcumin* / pharmacology
Extracellular Vesicles*
Inflammation / drug therapy
Mice
Rats

Substances

Albumins
Anti-Inflammatory Agents
Curcumin