Remotely Sequential Activation of Biofunctional MXenes for Spatiotemporally Controlled Photothermal Cancer Therapy Integrated with Multimodal Imaging

Abstract Spatiotemporally controlled cancer therapy may offer great advantages in precision medicine, but still remains some challenges in programmed sequential release and co‐localization of components at target sites. Herein, a MXene‐based nanoprobe (TCC@M) is meticulously designed by engineering of photodynamically activated CRISPR‐Cas9 and cancer cell membrane‐camouflaged Ti₃C₂ MXenes for targeting delivery and spatiotemporally controlled gene regulation followed by enhanced photothermal therapy (PTT) via two near‐infrared irradiations. The first irradiation can activate the photosensitizer bound in cancer cells internalized TCC@M to release Cas9 ribonucleoprotein (RNP) by photodynamic effect. The released Cas9 RNP then enters the nuclei directed by the fused nuclear localization sequence in Cas9 to cleave the heat shock protein (HSP) 90α gene, which greatly reduces the expression of HSP90α protein and thus effectively sensitizes cancer cells to heat, leading to enhanced PTT at a mild temperature (<45 °C) risen by Ti₃C₂ MXenes under the second irradiation. Simultaneously, TCC@M can produce fluorescence, photoacoustic, and thermal imaging signals to guide the optimal irradiation timing. The in vivo studies have demonstrated the spatiotemporally selective therapeutic efficacy of the designed TCC@M. This innovative approach presents an effective integration of gene regulation and enhanced PTT, exemplifying a precise cancer treatment strategy.