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

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.