Here, we report the enzyme-instructed supramolecular LYTAC that achieves LTRs-independent lysosomal targeting through an innovative self-assembly mechanism. Our rationally designed monomer possesses three key components: a self-assembly motif, an alkaline phosphatase-responsive moiety, and protein-of-interest binding ligand. The monomer self-assembles into an inert nanostructure, but it can transform into active form with increased positive charge and hydrophobicity after phosphate cleavage. EIS-LYTAC could further co-assemble with POI to generate nanocomplex, followed by endocytosis into lysosome via lipid raft mediated endocytosis in ALP expressing cells. This occurs in response to ALP primarily localized in the lipid raft domain, thereby enhancing lipid raft interactions in proximal region. This study fundamentally expands the toolkit for targeted protein degradation, offering unprecedented opportunities to design next-generation therapeutic interventions.