Redox-Induced Polymeric Micelle-to-Coacervate Transition for Enhanced Endosomal Escape, Prolonged Drug Retention, and Improved Sequential Drug Delivery

Abstract Polymeric micelles (PMs) and coacervate microdroplets (CMs) are both promising delivery vehicles, yet each suffers from distinct limitations. The delivery efficiency of PMs is often hindered by factors, such as limited endosome escape and uncontrolled drug release. On the other hand, CMs are prone to coalescence and aging, which hamper long-term storage and systemic injection. Here, by employing an intracellular morphological transition strategy, these drawbacks can be efficiently addressed without compromising their inherent advantages. The system exists as nanosized PMs during storage and circulation. Upon internalization by the tumor cells, the highly reductive intracellular environment induces the detachment of the poly(ethylene glycol) (PEG) shell and results in in situ formation of CMs. The formed CMs can effectively escape from endosomes by disrupting the endosomal membrane, facilitating the release of drugs into the cytoplasm. Furthermore, the CMs can serve as drug reservoirs, protecting the cargo from burst release and degradation, thus significantly prolonging the retention time and improving systemic delivery efficacy. Notably, the CMs can also sequester free drugs from the surrounding environment, enhancing sequential therapy by increasing the intratumoral accumulation of the temporally staggered agents. Thus, this micelle-to-coacervate transformable platform illuminates new possibilities for both types of drug-delivery systems.