Delivering Degradation: Nanomedicine and Programmable Proximity Platforms for Targeted Protein Degradation.

Targeted protein degradation (TPD) represents a whole new paradigm in cell-level therapeutic design, with its ability to remove target proteins, normally through the endogenous proteasomal, lysosomal, or autophagic systems, rather than the traditional occupancy-driven inhibition approach. But the clinical efficacy of degraders is becoming more restricted based on delivery rather than efficacy only. Many proteolysis-targeting chimeras and new proximity-inducing systems have low solubility, are impermeable, are pharmacodynamically complicated, lack tissue selectivity, and cannot fully access the intracellular space. Nanomedicine and PD platforms could provide strategies not only to overcome these challenges, but also to provide other advantages, including enhancing exposure to degraders, biodistribution, controlled release, and context-dependent activation. This critical review is an outline of all lipid, polymeric, inorganic, biomimetic, targeted, activatable, and self-assembling delivery systems for TPD. We assess compositional considerations, in vitro and in vivo evidence, challenges for translation, and clinical endpoints required to support delivery-enabled degradation. Trusted TPD therapeutics need to relate different aspects of their design, such as degrader chemistry, carrier structure, disease biology, and pharmacodynamic biomarkers, to one another. Further investigations are needed to establish intact delivery of the degrader to the target, target depletion in relevant tissues, prolonged pharmacodynamics, favorable safety, and compelling therapeutic benefit relative to free degraders or traditional inhibitors. Thus, it is important to view delivery not simply as an additional step during formulation but as a design principle necessary for the reliable clinical outcome of degradation medicine.