OBJECTIVE To summarize the synergistic penetration-enhancing mechanisms, key technical routes and translational progress of microneedle-assisted ultrasound-enhanced transdermal drug delivery, and to evaluate its application potential in overcoming the stratum corneum barrier and improving the delivery efficiency of hydrophilic and macromolecular drugs.

METHODS Recent relevant literatures in the field of microneedle and ultrasound permeation enhancement were retrieved and summarized, and classified and sorted out according to strategies such as sequential application, integrated/wearable platforms, ultrasound-responsive materials, and multiphysics synergy; from the dimensions of ultrasound frequency, acoustic intensity, duty cycle and exposure duration, as well as microneedle geometric parameters, drug loading modes and ultrasound-responsive carrier characteristics, the influence rules of various factors on drug delivery flux, penetration depth, onset time and safety were systematically summarized.

RESULTS Reversible microchannels created by microneedles, together with ultrasound-induced cavitation and microstreaming, synergistically increased the transdermal flux and shorten the onset time. Integrated and wearable delivery schemes improved delivery consistency and supported quantitative and repeatable drug administration. Ultrasound-responsive materials and multiphysics combinations could realize on-demand drug triggering, in situ activation and improved local exposure control, and had currently shown good application prospects in the directions of infectious diseases treatment, tumor therapy, immunomodulation, analgesic and anti-inflammation, as well as proteins/nucleic acids delivery.

CONCLUSION The quantitative interpretation of mechanistic, standardization of parameter windows and evaluation metrics, safety verification of long-term and repeated use, as well as device integration with quality consistency control are the keys to the clinical translation of microneedle-assisted ultrasound transdermal drug delivery. Future efforts should focus on reproducible parameterization and high-quality clinical evidence to facilitate engineering and productization.