CD28-Targeted Enzyme-Responsive Conformation-Switching Peptide Self-Assembly for Selective T-cell acute lymphoblastic leukemia (T-ALL) Therapy

CD28, a costimulatory receptor aberrantly overexpressed on T-ALL cells, presents a promising underexplored therapeutic target. In this study, we developed a modular enzyme-responsive self-assembling peptide, SAp-CD28, designed to selectively target CD28 and undergo receptor-mediated self-assembly in the tumor microenvironment.

Upon dephosphorylation by overexpressed phosphatases, SAp-CD28 transitions from an α-helix to a β-sheet/β-turn rich structure, facilitating the formation of nano-oligomers that engage CD28 and activate cytotoxic pathways. Transcriptomic profiling revealed two key mechanisms: PLCγ1 pathway degradation and Akt signaling suppression, leading to calcium overload, cytoskeletal collapse, and necrotic cell death. Besides, confocal imaging suggested that the peptide self-assembly can enter the nucleus and disrupt it.