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Optically active nanomaterials have shown great promise as a nanomedicine platform for photothermal or photodynamic cancer therapies. Herein, we report a gold-nanoclustered hyaluronan nanoassembly (GNc-HyNA) for photothermally boosted photodynamic tumor ablation. Unlike other supramolecular gold constructs based on gold nanoparticle building blocks, this system utilizes the nanoassembly of amphiphilic hyaluronan conjugates as a drug carrier for a hydrophobic photodynamic therapy agent verteporfin, a polymeric reducing agent, and an organic nanoscaffold upon which gold can grow. Gold nanoclusters were selectively installed on the outer shell of the hyaluronan nanoassembly, forming a gold shell. Given the dual protection effect by the hyaluronan self-assembly as well as by the inorganic gold shell, verteporfin-encapsulated GNc-HyNA (Vp-GNc-HyNA) exhibited outstanding stability in the bloodstream. Interestingly, the fluorescence and photodynamic properties of Vp-GNc-HyNA were considerably quenched due to the gold nanoclusters covering the surface of the nanoassemblies; however, photothermal activation by 808 nm laser irradiation induced a significant increase in temperature, which empowered the PDT effect of Vp-GNc-HyNA. Furthermore, fluorescence and photodynamic effects were recovered far more rapidly in cancer cells due to certain intracellular enzymes, particularly hyaluronidases and glutathione. Vp-GNc-HyNA exerted a great potential to treat tumors both in vitro and in vivo. Tumors were completely ablated with a 100% survival rate and complete skin regeneration over the 50 days following Vp-GNc-HyNA treatment in an orthotopic breast tumor model. Our results suggest that photothermally boosted photodynamic therapy using Vp-GNc-HyNA can offer a potent therapeutic means to eradicate tumors.

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TAPOs are frequently observed with osimertinib treatment and may be mistaken for isolated pulmonary progression or drug-induced ILD. Given the lack of serious clinical deterioration, it is reasonable to continue osimertinib with regular computed tomographic-scan follow-up. For further clinical validation of TAPOs, long-term follow-up and large studies are warranted.

To develop a successful HA-based nanomedicine, it has to be prepared without significant deterioration of intrinsic property of HA. The chemical modification of HA with drugs or hydrophobic moieties may reduce the binding affinity of HA to the receptors. In addition, since the HA-based nanomedicines tend to accumulate in the liver after their systemic administration, new strategies to overcome this issue have to be developed.

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