"Artificial platelet injection system": a plug-and-play platelet-based lysosome-targeting chimera for targeted protein degradation.

Targeted protein degradation technology via lysosomal machinery has attracted extensive attention due to its capability of degrading extracellular and membrane-associated proteins. Conventional lysosome-based degraders are established by conjugating bifunctional chimaeras, which requires complex multi-step synthesis and time-consuming purification. Isolated activated platelets have been found to target and be engulfed by tumor cells, raising the possibility of being harnessed for intracellular payload injection. Here, inspired by injection systems of endosymbiotic bacteria and bacteriophages, we develop an "artificial platelet injection system", a plug-and-play platelet-based lysosome-targeting chimera (PLT-TAC) via a facile microfluidic approach. PLT-TACs are meticulously manufactured by anchoring protein ligands and lysosome-sorting signal peptides onto activated platelet membrane, and can be easily optimized by tuning the peptide ratio on platelets to pursue the efficient protein degradation. Once PLT-TACs adhere to the tumor cytomembrane, they can be internalized into cells, and lysosome-sorting peptides initiate the "injection" of targeted proteins into lysosomes, thereby promoting the lysosomal degradation process. To test our concept, we use a peptide ligand targeting the immune checkpoint PD-L1 to engineer PLT-TACs. Efficient degradation of PD-L1 is confirmed both in vitro and in vivo. Furthermore, PLT-TACs can also degrade other proteins by simply installing alternative ligands. Our study proposes a new autologous cell-based protein degrader, with broad applicability in research and clinical practice.