In this study, gold nanorods (GNRs) were incorporated into the hydrogel networks formed by the copolymerization of N-isopropylacrylamide (NIPAm) and methacrylated poly-β-cyclodextrin (MPCD)-based macromer to fabricate an injectable and near-infrared (NIR)/pH-responsive poly(NIPAm-co-MPCD)/GNRs nanocomposite hydrogel, which could serve as a long-acting implant for chemophotothermal synergistic cancer therapy. The nanocomposite hydrogel showed superior mechanical and swelling properties, gelation characteristics, and excellent NIR-responsive property. A hydrophobic acid-labile adamantane-modified doxorubicin (AD-DOX) prodrug was loaded into the hydrogel efficiently by host-guest interaction. The nanocomposite hydrogel exhibited a manner of sustained drug release and could sustain the slow and steady release of DOX for more than 1 month. The pH-responsive release of DOX from the nanocomposite hydrogel was observed owing to the cleavage of acid-labile hydrazone bond between DOX and the adamantyl group in acidic environment. NIR irradiation could accelerate the release of DOX from the networks, which was controlled by the collapse of the hydrogel networks induced by photothermal effect of GNRs. The in vitro cytotoxicity test demonstrated the excellent biocompatibility and photothermal effect of the nanocomposite hydrogel. Moreover, the in situ-forming hydrogel showed promising tissue biocompatibility in the mouse model study. The in vivo antitumor test demonstrated the capacity of the nanocomposite hydrogel for chemophotothermal synergistic therapy with reduced adverse effects owing to the prolonged drug retention in the tumor region and efficient photothermal effect. Therefore, this injectable and NIR/pH-responsive nanocomposite hydrogel exhibited great potential as a long term drug delivery platform for chemophotothermal synergistic cancer therapy.

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A stimuli-responsive nanoplatform achieves successful intracellular siRNA delivery due to a proton sponge effect based on poly(l-histidine) and effective gene silencing in vivo.