Lysosome‐Targeted and Fluorescence‐Turned “On” Cytotoxicity Induced by Alkaline Phosphatase‐Triggered Self‐Assembly

Abstract Selectively inducing lysosomal membrane permeabilization (LMP) is a promising strategy for cancer therapy. But integrating alkaline phosphatase (ALP)‐instructed self‐assembly and lysosome‐targeting to induce LMP for selective killing of cancer cells was not reported. Herein, a pyrene‐peptide conjugate Py‐Phe‐Phe‐Glu‐Tyr(H 2 PO 3 )‐Gly‐lyso (Py‐Yp‐Lyso) is rationally designed and demonstrated for its lysosome‐targeting cytotoxicity on cancer cells, together with its pyrene (Py) excimer fluorescence turning “on” at 480 nm. In vitro results showed that, Py‐Yp‐Lyso is efficiently dephosphorylated by ALP to yield Py‐Phe‐Phe‐Glu‐Tyr‐Gly‐lyso (Py‐Y‐Lyso) which self‐assembles into nanofibers. Cell experiments verified that, after being taken up by HeLa cells, the excimer fluorescence of Py‐Yp‐Lyso assemblies has turned “on” and the assemblies specifically target the lysosomes, inducing LMP and ultimate cancer cell death. In vivo experiments indicated that Py‐Yp‐Lyso has the highest inhibition effect on HeLa tumors among the four compounds studied. This is anticipated for applying Py‐Yp‐Lyso to treat cancers in the clinic in the future.