Enhanced intracellular delivery of multi-responsive and size-switchable nanoparticles via microneedles for targeted psoriasis therapy.

Insufficient intracellular drug delivery to keratinocytes, which are hyper-proliferative and rich in reactive oxygen species (ROS), hinders effective treatment of psoriasis. This challenge largely results from the conflicting size requirements for dermal retention and efficient cellular uptake. We develop a microneedle-mediated delivery platform utilizing multi-responsive, keratinocyte-targeted, dynamically size-switchable NPs for psoriasis therapy. First, a dopamine-methotrexate conjugate (DMTX) is engineered, integrating both ROS-scavenging and anti-proliferative activities. By selectively modifying hyaluronic acid with phenylboronic acid derivatives and utilizing boron‑nitrogen coordination interactions, we have developed responsive HPD6 NPs (∼196 nm). These nanoparticles enhance uptake in keratinocytes by targeting CD44 and releasing DMTX in the mildly acidic, H2O2-rich environment of psoriatic plaques, forming smaller nanoparticles (∼26 nm) that facilitate intracellular delivery. Microneedle-facilitated HPD6 NPs administration demonstrates prolonged skin retention and substantial alleviation of epidermal thickening, inflammation, and T-cell infiltration in psoriasis models. This integrated approach represents a significant advancement in transdermal therapeutic strategies for addressing skin disorders.