Click Reaction-Based Afterglow Signal Activation and Nanoparticle Size Tunability for Precise Lung Cancer Imaging and Therapy

Early diagnosis and on-demand therapy remain formidable challenges in lung cancer treatment. The nonspecific uptake of nanomaterials by the reticuloendothelial system results in an extremely low signal-to-noise ratio for traditional probes with constant size and “always on” imaging signals, thereby impeding precise lung cancer theranostics. Herein, we design a tumor microenvironment (TME)-responsive nanoprobe, PLNP-N3/Alk@Cu2+, which boasts luminescence signal activation and size self-regulation for lung cancer imaging and chemodynamic therapy (CDT). It comprises ultrasmall persistent luminescence nanoparticles (PLNPs), azide and alkyne ligand-functionalized PEG shell, and Cu2+. The ultrasmall size and PEG coating endow the nanoprobe with excellent biocompatibility and prolonged blood circulation. In situ excitation-free properties of PLNPs along with a Cu2+-induced optical quenching effect constructs a TME-activated afterglow imaging mode, effectively minimizing background autofluorescence and false-positive signals. The combination of azide, alkyne, and Cu2+ ensures that self-assembly occurs exclusively in the glutathione-overexpressed TME, reducing nonspecific uptake and enhancing long-term retention at tumor sites. Moreover, the resulting Cu+ triggers CDT to achieve an efficient treatment. The intelligent nanoprobe ingeniously transforms the nonspecific uptake of nanoparticles in the lungs and the catalyst-triggered click reaction into advantages, enabling precise imaging and enhanced therapeutics without side effects, thereby showing excellent prospects for practical applications.