Enzyme-Responsive Peptide-Prodrug Integrated Biphasic Microneedle Patch for Enhanced Transdermal Delivery and Hypertension Therapy.

Hypertension is a major risk factor for cardiovascular diseases and needs effective blood pressure reduction. Current antihypertensive drugs, such as captopril, face challenges, including the enzymatic degradation and the liver first-pass effect. Here, we developed a dissolving microneedle (MN) loaded with a peptide-based enzyme-responsive prodrug peptide-captopril (PC) to enhance the stability of captopril and enable efficient transdermal delivery. Kinetic studies revealed that PC exhibited a lower value (1.1 × 10 M) for esterase-mediated hydrolysis compared to free captopril (2.1 × 10 M), indicating improved enzymatic stability. Meanwhile, PC was encapsulated stably in microneedle tips to form the PC MN, achieving approximately 90% transdermal drug delivery. In spontaneously hypertensive rat models, PC MN elicited a rapid and potent blood-pressure-lowering effect, outperforming oral captopril administration. This study presents a promising self-administering strategy to enhance hypertension treatment through efficient transdermal drug delivery.