UW-Madison researchers have developed an integrated targeted protein degrader (TPD) platform using chemically engineered endogenous platelets. The platform is constructed by grafting ubiquitin-proteasome system (UPS)- and lysosome-mediated TPD constructs into endogenous platelets. A protein of interest (POI) ligand was covalently tethered to heat shock protein 90 (HSP90) within platelets through a facile chemistry method. The resultant proteolytic platelets, termed DePLT, inherently and selectively accumulate at wound-associated disease sites where they potently degrade the POI by repurposing molecular chaperones in protein processing. Distinct POI ligands tethered within the activated DePLT are used to package and target HSP90 into platelet-derived microparticles, which are subsequently transferred to target cells via membrane fusion. Once fused, the labeled HSP90 captures intracellular POI, triggering USP-mediated degradation. Alternatively, POI ligand-tethered free HSP90 can be released to the surrounding environment where it can bind to extracellular POI, resulting in endosome-lysosome degradation. Together, these TPD approaches provide potent approaches for selective treatment of disease.