Driving Drugs Deeper: Force-Driven Microneedle Systems for Active Therapy and Their Road Towards Clinical Implementation.

Transdermal delivery of macromolecules and biologics is constrained by the barrier function of skin. First-generation microneedle arrays address this issue by penetrating the stratum corneum; however, their passive, diffusion-based release limits delivery depth, kinetics, and adaptability. In this review, we discuss force-driven microneedles (F-MNs) as a shift from passive permeation to active propulsion. F-MNs integrate mechanisms that generate localized physical driving forces to rapidly and controllably drive therapeutic payloads into tissue, achieving millimeter-scale penetration within seconds to minutes. We categorize four principal modalities based on their force-generation mechanism: gas-driven microneedles, cavitation-driven microneedles, magnetically actuated microneedles, and iontophoresis-enhanced microneedles. For each class, underlying mechanisms, material choices, safety considerations, and translational challenges are presented. We further discuss how artificial intelligence can guide F-MNs' design, manufacturing and closed-loop theranostic control. We also highlight the unique fabrication requirements of F-MNs, including multi-material integration, spatial compartmentalization of force-generating components, stimulus-responsive architectures, and device-level quality control. By framing F-MNs around their force-generation mechanisms and translational barriers, this review outlines design rules and clinical application spaces for deep, rapid, and controllable microneedle-mediated therapy across transdermal, mucosal, gastrointestinal, wound, and tumor-related delivery settings.