Peptide‐Drug Conjugate with Statistically Designed Transcellular Peptide for Psoriasis‐Like Inflammation

Peptide‐drug conjugates (PDCs) are a promising class of drug delivery systems that utilize covalently conjugated carrier peptides with therapeutic agents. PDCs offer several advantages over traditional drug delivery systems including enhanced target engagement, improved bioavailability, and increased cell permeability. However, the development of efficient transcellular peptides capable of effectively transporting drugs across biological barriers remains an unmet need. In this study, physicochemical criteria based on cell‐penetrating peptides are employed to design transcellular peptides derived from an antimicrobial peptides library. Among the statistically designed transcellular peptides (SDTs), SDT7 exhibits higher skin permeability, faster kinetics, and improved cell permeability in human keratinocyte cells compared to the control peptide. Subsequently, it is found that 6‐Paradol (PAR) exhibits inhibitory activity against phosphodiesterase 4, which can be utilized for an anti‐inflammatory PDC. The transcellular PDC (SDT7‐conjugated with PAR, named TM5) is evaluated in mouse models of psoriasis, exhibiting superior therapeutic efficacy compared to PAR alone. These findings highlight the potential of transcellular PDCs (TDCs) as a promising approach for the treatment of inflammatory skin disorders. Transcellular peptides (SDTs) derived from antimicrobial peptides are designed based on cell‐penetrating peptides for efficient delivery through the skin barrier. 6‐Paradol (PAR) is conjugated with SDT7 to treat psoriatic skin inflammation by inhibiting phosphodiesterase 4. The transcellular peptide‐drug conjugate (TM5) exhibits superior efficacy in psoriasis mouse models suggesting a promise for treating inflammatory skin disorders.