PhAc-ALGP-Dox

Bioorthogonal pre-targeting alleviate the limitations of traditional nanomedicines in passive and active targeting delivery. However, the high selectivity of bioorthogonal pre-targeting depends on the high expression level of antigens in lesion sites, and there are very limited targets with sufficient overexpression. Herein, we propose a tumor heterogeneity-independent antigen-responsive nanocarrier utilizing bioorthogonal pre-targeting and click-activated self-immolative polymers for stimulus signal conversion and amplification. This approach comprises a tetrazine (Tz) conjugated with trastuzumab (T-Tz), and a bioorthogonally activatable nanocarrier CONP which self-assembled by isocyanide and polyethylene glycol-modified poly (thiocarbamate) (NC-PTC-PEG) and hydrogen sulfide (H₂S)-responsive self-immolative polymers. In practice, T-Tz is first injected to actively pretarget HER2-positive tumor cells and followed by the second injection of nanocarrier CONP. The NC-PTC-PEG in CONP undergoes a click reaction with Tz to generate H₂S, thereby achieving the transformation from antigen signal to H₂S signal. Finally, NO₂-PTC-PEG responds to H₂S stimulation and undergoes a head-to-tail depolymerization process similar to dominoes to produce a large amount of H₂S, further amplifying the stimulus signal. This bioorthogonal pre-targeting combine with click-activated self-immolative polymers is anticipated to enhance the effectiveness of existing pre-targeting strategies for tumor imaging and therapy, with the potential to overcome challenges posed by tumor heterogeneity.