Deep-Penetrating Transdermal Lipopeptide Liposomes for Sustained IL-17 Inhibition and Prevention of Psoriatic Recurrence.

Psoriasis is a multisystemic, immune-mediated inflammatory disease characterized by high recurrence rates upon treatment cessation. Biotherapeutics are highly anticipated for treating psoriasis via transdermal delivery. However, the topical administration of potent immunomodulators is fundamentally hindered by the stratum corneum barrier, stringent molecular size constraints, and rapid proteolytic degradation within the skin microenvironment. Here, we report the development of transdermal lipopeptide liposomes (TLLs) designed for the site-specific delivery of a double-bridged cyclic tetradecapeptide (CTP)─a metabolically stable inhibitor of interleukin-17 (IL-17). The TLL platform utilizes engineered, asymmetric Y-shaped lipopeptides that transiently disrupt keratin and lipid organization, facilitating deep-seated penetration into psoriatic lesions. We demonstrate that protease-resistant CTP enables sustained antagonism of the IL-17 axis. In a preclinical model, TLL treatment significantly alleviated inflammatory symptoms and, crucially, suppressed rebound pathology and disease recurrence by remodeling both the local immune landscape and cutaneous biomechanics. This work establishes a clinically translatable framework that bridges the high efficacy of systemic biologics with the localized convenience of topical delivery, offering a transformative, patient-centric alternative to parenteral biologic therapies.