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Epidermal SR-A Complexes Are Lipid Raft Based and Promote Nucleic Acid Nanoparticle Uptake.

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Scavenger receptors, like SCARA3 and MARCO, facilitate the skin penetration of topical spherical nucleic acid (SNA) nanoparticles. These receptors are crucial for SNA uptake via active endocytosis within epidermal lipid rafts.

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Area of Science:

  • Dermatology
  • Nanotechnology
  • Immunology

Background:

  • Scavenger receptors (SRs) are vital in macrophages for pathogen clearance and lipid transport, but their function in skin remains unclear.
  • The skin's epidermal barrier typically prevents the entry of nucleic acids, limiting their topical application.
  • Spherical nucleic acids (SNAs) are novel nanoconjugates designed for potential topical delivery.

Purpose of the Study:

  • To investigate the mechanism of SNA uptake in human skin and skin equivalents.
  • To identify the specific scavenger receptors involved in SNA penetration through the epidermis.
  • To elucidate the cellular pathways and localization of SRs mediating SNA uptake.

Main Methods:

  • Utilized normal human epidermal keratinocytes and 3D skin equivalents for in vitro and ex vivo studies.
  • Employed SR-A inhibitors and lentiviral knockdown to assess the role of specific SRs (SCARA3, MARCO).
  • Applied endocytosis inhibitors, immunofluorescence, and immunoprecipitation to study SNA uptake mechanisms and SR localization.

Main Results:

  • Topical SNA uptake in keratinocytes and 3D skin rafts was significantly reduced (>80%) by SR-A inhibitors.
  • Human epidermis expresses SCARA3 and MARCO, and their simultaneous knockdown impaired SNA uptake.
  • SNA uptake was dependent on active endocytosis and functional SRs localized to FLOT-1 and CAV-1 containing lipid rafts in the epidermis.

Conclusions:

  • Scavenger receptors, particularly SCARA3 and MARCO, play a critical role in mediating the epidermal uptake of topical SNAs.
  • SNA penetration into the skin involves active endocytosis and relies on the localization of SRs within epidermal lipid rafts.
  • These findings highlight the potential of SR-mediated pathways for topical nanoparticle delivery to the skin.