From nanoengineering to microphysiology: Organ-on-chip platforms for next-generation drug delivery

Nanoparticle-based drug delivery has a transformative role in therapeutic design by enabling targeted transport, controlled release, and enhanced pharmacokinetics. Traditional in vitro and animal models often fail to capture the dynamic, multicellular, and biomechanical complexity of human tissues, limiting their predictive value for translational nanomedicine. Organ-on-chip (OoC) technologies bridge this gap by recreating physiologically relevant microenvironments that integrate fluid flow, mechanical stimulation, and tissue-specific architecture, allowing nanoparticle behavior to be studied under human-relevant conditions. In this review, we provide a mechanistic framework for understanding of the interaction of nanoparticle therapeutics with microphysiological systems. We first discuss design principles of major nanoparticle platforms and highlight the effects of nano–biointerface dynamics, including protein corona formation and immune interactions, on transport and efficacy in drug delivery. A major focus of the review is on stimuli-responsive and adaptive delivery strategies, including pH-, thermal-, electrical-, magnetic-, optical-, and sensor-integrated systems and on the role of OoC platforms in quantitative evaluation of triggered release and therapeutic response in real time. We then examine organ-specific OoC models, including spanning lung, liver, heart, gut, and blood–brain barrier systems, which are helpful in explaining the regulation of nanoparticle biodistribution and therapeutic performance by tissue mechanics and physiological gradients. We further discuss emerging directions such as computational integration, digital biomarkers, and regulatory translation and the transformation of drug delivery research thanks to the synergy of nanotechnology, microphysiological engineering, and data-driven modeling. In contrast to previous reviews, this work integrates nanoparticle design, nano–biointerface dynamics, and organ-specific OoC systems to provide a mechanistic framework for evaluating and optimizing next-generation nanomedicine delivery. This review positions organ-on-chip systems as predictive design environments that not only model human physiology but also enable rational optimization of next-generation nanomedicines, accelerating the development of safer, more effective, and personalized therapeutic strategies.