Development of Stable and Intensified Mixing Processes for the Precise and Scalable Production of Uniform Drug Delivery Nanocarriers

Abstract Nanocarriers show great promise in drug delivery but face challenges in stability, uniformity, and morphology control. This work introduces an enhanced mixing process to overcome these obstacles, specifically aiming to produce consistently sized poly(lactic‐co‐glycolic) acid (PLGA) nanoparticles loaded with anti‐tumor drugs. By innovatively integrating a pulsation dampener into the microfluidic channels of a continuous flow preparation system, the flow stability of piston pumps is improved nearly tenfold. Consequently, large‐scale production of uniformly sized nanoparticles with customizable dimensions is achieved through nanoprecipitation. Furthermore, incorporating terminal double‐bond‐functionalized poly(lactic‐co‐glycolic acid)‐b‐poly(ethylene glycol)‐maleimide (PLGA‐PEG‐Mal) enables these nanoparticles to act as nano‐crosslinkers. This facilitates in situ crosslinking with thiolated hyaluronic acid via a spontaneous thiol‐ene coupling reaction under physiological conditions, allowing for minimally invasive drug administration and significantly enhancing localized drug retention. The material's degradability in the presence of endogenous enzymes ensures controlled drug release, as demonstrated with the anti‐tumor drug doxorubicin (DOX). Validation in a murine breast cancer model shows reduced toxicity and a substantial reduction in tumor weight compared to the free DOX group. These findings confirm the approach's effectiveness for breast cancer treatment and pave the way for innovative solutions in nanomedicine, providing a practical microfluidic mixing system for the design and large‐scale production of nanomedicines.