Silk Fibroin Microneedles with Controlled Release Kinetics for Extended Protection Against Soman Intoxication

The rapid aging kinetics of soman (< 2 min) necessitate the development of effective prophylactic countermeasures, as conventional post-exposure therapies are often inadequate. To address this challenge, we engineered a novel separable microneedle (MN) system based on silk fibroin (SF) for sustained transdermal delivery of huperzine A (Hup A)—a reversible acetylcholinesterase inhibitor with demonstrated blood - brain barrier penetration capabilities. The optimized SFMNs design featured a distinctive tip-separation mechanism that facilitated reliable detachment of drug-loaded needle tips within 2 min after dermal application. The characterization results showed that the MN patch exhibited robust mechanical strength (155.49±11.18 N/patch), uniform morphology, effective skin penetration and homogeneous distribution of Hup A within the needle tips. Notably, the SFMNs platform provided controlled release kinetics, achieving sustained in vitro release of Hup A over 12 h, with an initial burst phase conducive to rapid drug onset. Pharmacokinetic evaluations in mice revealed that transdermal delivery via SFMNs (4 mg/kg Hup A) maintained therapeutic plasma concentrations for up to 12 h, significantly prolonging the mean residence time (11.87 ± 0.88 h) compared to oral administration (2.39 ± 0.31 h). This sustained-release profile markedly reduced systemic toxicity; whereas oral Hup A elicited severe cholinergic adverse effects (e.g., sweating, tremors), SFMNs-mediated delivery circumvented these toxic responses. In a prophylactic efficacy study, Hup A-loaded SFMNs (4 mg/kg) conferred complete protection (100% survival) for 12 h against a 95% lethal dose soman challenge, substantially extending the protective window compared to both oral Hup A (2 h) and intramuscular pyridostigmine bromide (45 min). These findings demonstrate that the SFMNs platform represents a promising, convenient, and well-tolerated strategy for long-acting prophylaxis against soman intoxication.