Coating Janus Nanoparticles with Immunoregulatory Protein Embedded Membrane for Enhanced Anti-Inflammatory and Sonodynamic Therapy of Psoriasis.

Abstract

The interplay between keratinocyte (KC) hyperproliferation and T cell activation underpins psoriasis pathogenesis, posing significant challenges for effective treatment. Here, cell membrane-coated nanoparticles (CNPs) are designed to simultaneously inhibit T cell activation and KC hyperproliferation for optimized psoriasis therapy. A customized cell membrane is genetically engineered to overexpress the immunoregulatory V-domain immunoglobulin suppressor of T cell activation (VISTA) protein to enable potent T-cell inhibition. The encapsulated core is designed as Janus nanoparticles (mSiO&rPMO) for co-delivery of hydrophilic 5-aminolevulinic acid (5-ALA) and hydrophobic tazarotene, facilitating synergistic sonodynamic therapy (SDT) and anti-inflammatory effects. Mechanistically, under ultrasound stimulation, accumulated protoporphyrin IX (PpIX) derived from 5-ALA metabolism generates reactive oxygen species (ROS) that inhibit epidermal proliferation, while tazarotene activates retinoic acid receptor gamma (RARγ) to exert anti-inflammatory effects. Concurrently, the VISTA-overexpressed membrane enhances anti-inflammatory responses, further amplifying the anti-psoriatic effect. CNP efficacy in a psoriatic mouse model is validated, demonstrating mitigated lesion severity, suppressed epidermal hyperplasia, and reduced inflammatory cytokine levels in skin lesions. Notably, CNPs outperformed non-membrane counterparts in both cellular and animal models, highlighting the anti-psoriatic amplification conferred by the engineered membrane. Overall, this research presents a novel therapeutic strategy for psoriasis management using engineered membrane-coated mesoporous Janus nanoparticles to target keratinocyte proliferation and T cell activation.