Multi-Scale Continuous-Flow Fluidic Strategies for Nanodrug Formulation, Engineering, and Delivery

Advances in milli-, micro-, and nanofluidic systems have transformed drug nanoparticle formation, each scale presenting distinct mixing and particle formation constraints. Millifluidics offer stability for formulation translation but limited operational tolerance. Microfluidics enable precise control over particle size and batch consistency via solvent exchange and micromixing. Nanofluidics, dominated by surface effects and molecular confinement, allow stimuli-triggered drug release (e.g., pH, heat) unattainable at larger scales. Emerging trends integrate all three scales into hybrid workflows, employ AI for process optimization, continuous manufacturing, and more biocompatible materials. Key challenges remain—channel clogging, material-dependent performance, narrow scale-up windows, and regulatory barriers to clinical translation. This review synthesizes progress across scales, identifies development needs, and explores future directions including multi-scale hybrid systems, smart process controls, and patient-tailored nanofluidic designs.