Peng Huang

The complexity, diversity, and heterogeneity of tumors seriously undermine the therapeutic potential of treatment. Therefore, the current trend in clinical research has gradually shifted from a focus on monotherapy to combination therapy for enhanced treatment efficacy. More importantly, the cooperative enhancement interactions between several types of monotherapy contribute to the naissance of multimodal synergistic therapy, which results in remarkable superadditive (namely "1 + 1 > 2") effects, stronger than any single therapy or their theoretical combination. In this review, state-of-the-art studies concerning recent advances in nanotechnology-mediated multimodal synergistic therapy will be systematically discussed, with an emphasis on the construction of multifunctional nanomaterials for realizing bimodal and trimodal synergistic therapy as well as the intensive exploration of the underlying synergistic mechanisms for explaining the significant improvements in synergistic therapeutic outcome. Furthermore, the featured applications of multimodal synergistic therapy in overcoming tumor multidrug resistance, hypoxia, and metastasis will also be discussed in detail, which may provide new ways for the efficient regression and even elimination of drug resistant, hypoxic solid, or distant metastatic tumors. Finally, some design tips for multifunctional nanomaterials and an outlook on the future development of multimodal synergistic therapy will be provided, highlighting key scientific issues and technical challenges and requiring remediation to accelerate clinical translation.

Nanozymes are nanomaterial-based artificial enzymes. By effectively mimicking catalytic sites of natural enzymes or harboring multivalent elements for reactions, nanozyme systems have successfully served as direct surrogates of traditional enzymes for catalysis. With the rapid development and ever-deepening understanding of nanotechnology, nanozymes offer higher catalytic stability, ease of modification and lower manufacturing cost than protein enzymes. Additionally, nanozymes possess inherent nanomaterial properties, providing not only a simple substitute of enzymes but also a multimodal platform interfacing complex biologic environments. Recent extensive research has focused on designing various nanozyme systems that are responsive to one or multiple substrates by tailored means. Catalytic activities of nanozymes can be regulated by pH, H2O2 and glutathione concentrations and levels of oxygenation in different microenvironments. Moreover, nanozymes can be remotely-controlled via different stimuli, including a magnetic field, light, ultrasound, and heat. Collectively, these factors can be adjusted to maximize the diagnostic and therapeutic efficacies of different diseases in biomedical settings. Therefore, by integrating the catalytic property and inherent nanomaterial nature of nanozyme systems, we anticipate that stimuli-responsive nanozymes will open up new horizons for diagnosis, treatment, and theranostics.

Photodynamic therapy (PDT) has been applied to treat a wide range of medical conditions, including wet age-related macular degeneration psoriasis, atherosclerosis, viral infection and malignant cancers. However, the tissue penetration limitation of excitation light hinders the widespread clinical use of PDT. To overcome this "Achilles' heel", deep PDT, a novel type of phototherapy, has been developed for the efficient treatment of deep-seated diseases. Based on the different excitation sources, including near-infrared (NIR) light, X-ray radiation, and internal self-luminescence, a series of deep PDT techniques have been explored to demonstrate the advantages of deep cancer therapy over conventional PDT excited by ultraviolet-visible (UV-Vis) light. In particular, the featured applications of deep PDT, such as organelle-targeted deep PDT, hypoxic deep PDT and deep PDT-involved multimodal synergistic therapy are discussed. Finally, the future development and potential challenges of deep PDT are also elucidated for clinical translation. It is highly expected that deep PDT will be developed as a versatile, depth/oxygen-independent and minimally invasive strategy for treating a variety of malignant tumours at deep locations.

Two-dimensional transition metal carbides and nitrides known as MXenes, with a general formula of Mn+1Xn (n = 1-3), integrate the advantages of metallic conductive transition metals with large groups of carbides, nitrides, or carbonitrides. They have led to a burgeoning research interest in biomedical applications due to their ultrathin structure and fascinating physiochemical (electronic, optical, magnetic, etc.) properties. In this review, we summarize recent advances in biomedical applications for MXenes. We first introduce the preparation methods and surface modifications with respect to MXenes. Their unique properties are then elaborated. Thirdly, we highlight their various biomedical applications, such as with biosensors, antibacterial materials, bioimaging probes, therapeutics, and theranostics. In the end, the current challenges and new opportunities for MXenes in regard to their biomedical applications are also discussed.

Abstract Chemodynamic therapy (CDT) is an emerging therapy method that kills cancer cells by converting intracellular hydrogen peroxide (H 2 O 2 ) into highly toxic hydroxyl radicals ( • OH). To overcome the current limitations of the insufficient endogenous H 2 O 2 and the high concentration of glutathione (GSH) in tumor cells, an intelligent nanocatalytic theranostics (denoted as PGC‐DOX) that possesses both H 2 O 2 self‐supply and GSH‐elimination properties for efficient cancer therapy is presented. This nanoplatform is constructed by a facile one‐step biomineralization method using poly(ethylene glycol)‐modified glucose oxidase (GOx) as a template to form biodegradable copper‐doped calcium phosphate nanoparticles, followed by the loading of doxorubicin (DOX). As an enzyme catalyst, GOx can effectively catalyze intracellular glucose to generate H 2 O 2 , which not only starves the tumor cells, but also supplies H 2 O 2 for subsequent Fenton‐like reaction. Meanwhile, the redox reaction between the released Cu 2+ ions and intracellular GSH will induce GSH depletion and reduce Cu 2+ to Fenton agent Cu + ions, and then trigger the H 2 O 2 to generate • OH by a Cu + ‐mediated Fenton‐like reaction, resulting in enhanced CDT efficacy. The integration of GOx‐mediated starvation therapy, H 2 O 2 self‐supply and GSH‐elimination enhanced CDT, and DOX‐induced chemotherapy, endow the PGC‐DOX with effective tumor growth inhibition with minimal side effects in vivo.