A dendritic drug–drug conjugate self-assembled hypoxia-responsive supramolecular nanoparticle for combination therapy†

Hypoxia, a condition that enhances tumor invasiveness and metastasis, poses a significant challenge for diverse cancer therapies. There is a pressing demand for hypoxia-responsive nanoparticles with integrated photodynamic functions in order to address the aforementioned issues and overcome the reduced efficacy caused by tumor hypoxia. Here, we report a hypoxia-responsive supramolecular nanoparticle SN@IR806-CB consisting of a dendritic drug–drug conjugate (IR806-Azo-CB₄) and anionic water-soluble [2]biphenyl-extended-pillar[6]arene modified with eight ammonium salt ions (AWBpP6) via the synergy of π–π stacking interaction, host–guest complexation, and hydrophobic interactions for synergistic photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy (CT; i.e., PTT–PDT–CT). Under near-infrared (NIR) irradiation, the IR806-based PTT and PDT could generate hyperthermia to thermally ablate tumor tissue and deplete oxygen to generate singlet oxygen (¹O₂), respectively. The resulting hypoxia exacerbation further accelerated the release of activated CB. Consequently, this nanoparticle could be a potential candidate for achieving significant therapeutic efficacy through PTT–PDT–CT.