Dynamic Effects of Endo–Exogenous Stimulations on Enzyme-Activatable Polymeric Nanosystems with Photo–Sono–Chemo Synergy

Activatable polymeric nanosystems have attracted great interest, and their interactions with endo–exogenous stimulations are highly vital for therapeutic efficacy, which urgently needs systematic study. Herein we focus on systematically investigating these interactions on an enzyme–nanosystem model, the tumor-overexpressed hyaluronidase (HAase) and the doxorubicin-loaded hyaluronic-acid-porphyrin nanoassemblies (DOX@HPNAs), to augment photo–sono–chemo therapies. The HAase degrades the HPNAs in acidic solution at a higher rate than that in neutral solution, which leads to structure disassembly at the nano level, chain cleavage at the molecular level, and strong radiative recovery at the energy level. Upon excitation with light and ultrasound, the enzymatically degraded sample produces ∼2.5 times more singlet oxygen than the HPNAs because of the absence of aggregation-induced quenching and 1O2 migration limitation. The nanosystem can be activated by trimodal stimulations (acidity, ultrasound, and HAase), exerting the controllable release behavior and high release content. Moreover, the nanosystem exhibits synergistic effects among efficient photodynamic therapy, high tissue-penetrating sonodynamic therapy, and lasting chemotherapy, which induces significant necrosis and apoptosis of cancer cells. With high compatibility, tumor-targeting ability, and fluorescent-imaging-guided capability, the nanosystem achieves the highest inhibition rate of malignant tumors than the single or dual-modal therapies. Thus, the enzyme-activatable nanosystem enables the therapeutic synergy and also provides insights to develop other polymeric nanosystems.