Bacterium-mimicking sequentially targeted therapeutic nanocomplexes based on O-carboxymethyl chitosan and their cooperative therapy by dual-modality light manipulation.

An integrated gene nanovector capable of overcoming complicated physiological barriers in one vector is desirable to circumvent the challenges imposed by the intricate tumor microenvironment. Herein, a nuclear localization signals (NLS)-decorated element and an iRGD-functionalized element based on O-carboxymethyl chitosan were synthesized, mixed, and coated onto PEI/DNA to fabricate bacterium-mimicking sequentially targeted therapeutic nanocomplexes (STNPs) which were internalized through receptor-mediated endocytosis and other pathways and achieved nuclear translocation of DNA. The endo/lysosomal membrane disruption triggered by reactive oxygen species (ROS) after short-time illumination, together with the DNA nuclear translocation, evoked an enhanced gene expression. Alternatively, the excessive ROS from long-time irradiation induced apoptosis in tumor cells, bringing about greater anti-tumor efficacy owing to the integration of gene and photodynamic therapy. Overall, these results demonstrated bacterium-mimicking STNPs could be a potential candidate for tumor treatments.