Click, assemble, destroy: Bioorthogonal surface programming of nanophotosensitizers for precision cancer therapy.

Phototherapy, a cutting-edge non-invasive cancer treatment, excels in precision and safety but suffers from poor tumor targeting. Bioorthogonal chemistry revolutionizes this field by enabling artificial molecular targets with unparalleled specificity to overcome these limitations and unlock its full therapeutic potential. Leveraging this unique capability, we designed a novel single-component phototherapeutic agent (C-SS-D) that integrates bioorthogonal reactivity to enhance tumor-specific delivery. This system self-assembles into nanoparticles, utilizing the enhanced permeability and retention (EPR) effect alongside a two-step targeting strategy -metabolic glycolabeling and bioorthogonal click chemistry - to achieve precise tumor accumulation of photosensitizers (PSs). Additionally, the disulfide bond in C-SS-D responds to elevated glutathione (GSH) levels in the tumor microenvironment, triggering a structural transformation that enhances in situ phototherapeutic efficacy while minimizing off-target effects, thereby broadening the therapeutic window. In vivo studies using a mouse model pretreated with tetraacetylated N-azidoacetyl-D-mannosamine (AcManNAz) demonstrated that C-SS-D exhibits remarkable tumor selectivity and potent phototherapeutic performance. This tumor-specific supramolecular phototherapy strategy, powered by bioorthogonal reactions, offers a versatile and broadly applicable platform with transformative potential - particularly for tumors lacking endogenous targeting receptors - paving the way for next-generation precision cancer therapies.