Chaotrope-guided protein microneedles with high drug-loading capacity, ultrafast dissolution, and high mechanical strength.

Abstract

Conventional dissolvable microneedles are plagued by an inherent trade-off between processability, mechanical robustness, and rapid dissolution kinetics, which severely restricts their clinical utility in time-critical therapeutic interventions. Inspired by the Hofmeister chaotropic effect, we herein engineered a novel class of chaotrope-induced protein microneedles that concurrently achieve ultrafast dissolution, exceptional mechanical strength, and preserved high bioactivity. Specifically, we fabricated iodide-modified gelatin microneedles (denoted as G₂₀I₁₀@) and systematically evaluated their biological performance in two clinically translatable scenarios: rapid local anesthesia and hair regeneration. In the local anesthesia model, the ultrafast dissolution kinetics of the microneedle matrix afforded an analgesic onset comparable to conventional injection, elevating the pain threshold to 310% of the baseline level within 15 min. In the androgenetic alopecia model, iodide functioned as an "immune-response amplifier", which synergized with microneedle-mediated microstimulation to remodel the perifollicular microenvironment-facilitating M2 macrophage polarization, activating hair follicle stem cells, and ultimately driving robust hair regrowth. Collectively, these findings establish a versatile protein-based microneedle platform that integrates dual functions as a delivery carrier and an intrinsic therapeutic agent, thereby advancing microneedles from a passive delivery tool to an active therapeutic strategy for regenerative medicine and time-sensitive clinical care. STATEMENT OF SIGNIFICANCE: 1) This study presents the development of a microneedle designed for immediate drug release, achieved through the modification of proteins with chaotropic agents. This innovation shows significant potential for clinical applications that necessitate rapid drug onset, such as anesthesia and swift anti-inflammatory treatment. 2) The shrinkage of high-concentration proteins during the drying process limits the application of such proteins in microneedles. In this study, the viscosity of the protein solution was reduced by modifying the protein with chaotropic agents, thereby creating favorable conditions for the precise fabrication of microneedles. This modification effectively prevented the contraction of protein microneedles and broadened the clinical application scenarios for protein-based microneedles. 3) This study found that the iodide component functions as an "immune response amplifier" and, in conjunction with microneedle mechanical stimulation, facilitates the M2 differentiation of macrophages, thereby promoting hair regrowth in androgenetic alopecia.