Modulating Cell Specificity and Subcellular Localization by Molecular Charges and Lipophilicity

The precise treatment of cancer requires maximized lesion to cancer cells and minimized damage to normal cells; however, the current theranostic nanomaterials have limited generic theranostic specificity to cancer cells. Herein, as a proof of concept, a small-molecular system simultaneously possessing on-site fluorescence light-up feature, universal cancer cell selectivity, controllable subcellular localization, and activated therapeutic function is developed for cancer theranostics. These molecular probes are composed of photosensitizers (PSs) with the aggregation-induced emission (AIE) feature as the core and aliphatic chains containing lipophilic cations as the arms, which show fluorescence light-up upon entering cancer cells. The charges and lipophilicity of these light-up probes are fine-tuned by the number of lipophilic cations, which modulate their cancer cell selectivity and subcellular localization, where the synthesized AIE PS with four positive charges (TPETM-4+) shows the highest differentiation toward all tested cancer cells over normal ones; neutrally charged TPETM-2 with two arms stains the cytoplasm, TPETM-2+ with two positive charges stains the mitochondria, while TPETM-4+ labels the lysosome. Moreover, under light irradiation, TPETM-4+ exhibits specific photodynamic ablation toward cancer cells over normal ones. This study proposes a new approach to design delivery systems for generic cancer cell selectivity with subcellular localization control, which opens up new opportunities for precise cancer therapy.