Dual-lock targeting strategy for precision psoriasis therapy: Receptor-locked and electro-gated exosome delivery

Psoriasis is a common chronic immune-mediated skin disease with recurrent scaly plaques that impair quality of life. Although drugs such as methotrexate have been developed for this disease, they often cause serious adverse effects, limiting long-term use. Here, we present a Dual-Lock Targeting (DLT) strategy at both the device and the cellular levels that integrates receptor-guided exosome homing with electric-field gating to localize therapy spatiotemporally. We engineer a folate-modified, methotrexate-loaded exosome (FPC@MtExo) and load it using a wearable, self-powered microneedle (SPMD) system. The microneedle patch provides site lock-in and time-gated release via an electric-field–gated interface, while simultaneously achieving receptor-locked targeting at the cellular level through immune-cell recognition of FPC@MtExo. In vitro, FPC@MtExo exhibits markedly increased uptake by macrophages compared with non-targeted exosomes; this effect is further enhanced under the SPMD system. In psoriatic mouse models, the DLT strategy significantly attenuates manifestations and improves histopathology while suppressing cutaneous inflammation. Importantly, the strategy reduces circulating free methotrexate, with AST/ALT approaching baseline, indicating mitigated hepatotoxicity and an improved therapeutic effect. By coupling receptor-mediated engineered exosome homing with electric-field gating in a wearable microneedle patch, the DLT strategy delivers spatiotemporally precise therapy that concentrates the drug at the lesion while minimizing systemic side effects. This approach provides a general path to safer, more effective treatment of psoriasis and other inflammatory skin diseases.