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The potential therapeutic implications of nitric oxide (NO) for diverse diseases have been under consideration for years; however, the development of precisely controllable NO generation system with potential for clinical application has remained elusive. Herein, intelligent near‐infrared (NIR) laser‐triggered NO nanogenerators for the treatment of multidrug‐resistant (MDR) cancer are fabricated by integrating photothermal agents and heat‐sensitive NO donors into a single nanoparticle. Such nanogenerators can absorb 808 nm NIR photons and convert them into ample heat to trigger NO release. The generated NO molecules are demonstrated to successfully achieve multidrug‐resistance reversal by inhibiting the expression of P‐glycol protein. Consequently, the intracellular accumulation of doxorubicin is effectively increased, resulting in high toxicity to MDR cancer cells in vitro. By virtue of surface modification with targeting ligands, these nanoparticles are able to selectively accumulate in tumor tissue. The therapeutic effects of the nanogenerators are validated in a humanized MDR cancer model. The in vivo experiment indicates that the nanoparticles possess excellent tumor suppression functionality with few side effects upon NIR laser exposure. Therefore, this novel photothermal conversion‐based NO‐releasing platform is expected to be a potential alternative to clinical MDR cancer treatment and may provide insights with regard to other NO‐relevant medical treatments.

Photothermal therapy (PTT) and photodynamic therapy (PDT) are promising cancer treatment modalities in current days while the high laser power density demand and low tumor accumulation are key obstacles that have greatly restricted their development. Here, magnetic composite nanoparticles for dual-modal PTT and PDT which have realized enhanced cancer therapeutic effect by mitochondria-targeting are reported. Integrating PTT agent and photosensitizer together, the composite nanoparticles are able to generate heat and reactive oxygen species (ROS) simultaneously upon near infrared (NIR) laser irradiation. After surface modification of targeting ligands, the composite nanoparticles can be selectively delivered to the mitochondria, which amplify the cancer cell apoptosis induced by hyperthermia and the cytotoxic ROS. In this way, better photo therapeutic effects and much higher cytotoxicity are achieved by utilizing the composite nanoparticles than that treated with the same nanoparticles missing mitochondrial targeting unit at a low laser power density. Guided by NIR fluorescence imaging and magnetic resonance imaging, then these results are confirmed in a humanized orthotropic lung cancer model. The composite nanoparticles demonstrate high tumor accumulation and excellent tumor regression with minimal side effect upon NIR laser exposure. Therefore, the mitochondria-targeting composite nanoparticles are expected to be an effective phototherapeutic platform in oncotherapy.

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Combination of photothermal therapy (PTT) and photodynamic therapy (PDT) has become a promising cancer treatment in recent years. However, their applications are limited by complex synthetic protocols and low efficacy. Hence, optimizing experimental approach and improving the efficiency of phototherapy is the current research focus. In this work, various pyrolysis temperatures and sizes of zeolitic imidazolate framework-8 (ZIF-8) derived carbon nanoparticles (ZCNs) are obtained by a simple direct pyrolysis of the ZIF-8 nanoparticles. Meanwhile, the ZCNs can be used as photothermal agents and photosensitizers to produce heat and reactive oxygen species simultaneously upon near-infrared laser irradiation. Moreover, it is observed that the phototherapy effects and photoacoustic (PA) signal of ZCNs could be enhanced with the increase in the nanoparticle size. Subsequently, guided by PA imaging, the therapeutic effect of ZCNs is investigated on a small animal model, where tumors are entirely eliminated with minimal side effect, demonstrating the high efficacy of the larger size of ZCNs through combination of PTT and PDT. Therefore, it is expected that the ZCN is a simple and highly effective phototherapeutic platform for oncotherapy, and the concept of size-dependent enhanced behavior of phototherapy and PA imaging will be very useful in the development of nanomaterials for cancer therapy.

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