Advancing PROTAC therapeutics through chemistry-guided design of smart delivery systems

Proteolysis-targeting chimeras (PROTACs) have redefined the paradigm of targeted protein degradation by hijacking the endogenous ubiquitin-proteasome system. However, their clinical translation remains hampered by “beyond-rule-of-five” (bRo5) physicochemical liabilities, including high polarity, limited membrane permeability, and unpredictable pharmacokinetic behavior, which collectively lead to suboptimal bioavailability and risks of non-specific systemic distribution. This review focuses on the chemistry-driven evolution of delivery strategies to transform these molecular liabilities into pharmacological advantages. By integrating medicinal chemistry with delivery science, we propose a conceptual framework to optimize target selectivity, enhance cellular uptake, and broaden the therapeutic window, providing systematic guidance for overcoming the bottlenecks of PROTAC in vivo applications. In terms of molecular design, innovations in prodrug and linker engineering, including photo-responsive, enzyme-activated, folate-targeted, and reactive oxygen species (ROS)-triggered systems, achieve precise spatiotemporal regulation and controlled release of PROTAC activity. The field of delivery vehicles encompasses lipid-based, polymeric, and inorganic nanoscaffolds, as well as antibody-PROTAC conjugates (DACs) and aptamer-PROTAC hybrids (APCs), providing multidimensional platforms for crossing biological barriers and achieving antigen-dependent targeting. Furthermore, the emergence of modular self-assembly, membrane-targeting strategies, and “split-and-hybrid” paradigms signifies a shift toward programmable medicinal chemistry that integrates physicochemical tuning with pharmacokinetic optimization. Future integration of chemically reconfigurable carriers with unified PK-PD evaluation systems will further accelerate the clinical translation of next-generation intelligent PROTAC therapeutics. (Figure presented.)