During the past two decades, the paradigm for cancer treatment has evolved from relatively nonspecific cytotoxic agents to selective, mechanism-based therapeutics. Cancer chemotherapies were initially identified through screens for compounds that killed rapidly dividing cells. These drugs remain the backbone of current treatment, but they are limited by a narrow therapeutic index, significant toxicities and frequently acquired resistance. More recently, an improved understanding of cancer pathogenesis has given rise to new treatment options, including targeted agents and cancer immunotherapy. Targeted approaches aim to inhibit molecular pathways that are crucial for tumour growth and maintenance; whereas, immunotherapy endeavours to stimulate a host immune response that effectuates long-lived tumour destruction. Targeted therapies and cytotoxic agents also modulate immune responses, which raises the possibility that these treatment strategies might be effectively combined with immunotherapy to improve clinical outcomes.

Nanoscience has long been lauded as a method through which tumor-associated barriers could be overcome. As successful as cancer immunotherapy has been, limitations associated with the tumor microenvironment or side effects of systemic treatment have become more apparent. In this Review, we seek to lay out the therapeutic challenges associated with the tumor microenvironment and the ways in which nanoscience is being applied to remodel the tumor microenvironment and increase the susceptibility of many cancer types to immunotherapy. We detail the nanomedicines on the cutting edge of cancer immunotherapy and how their interactions with the tumor microenvironment make them more effective than systemically administered immunotherapies.

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.

Burns are among the most common causes of trauma worldwide. Reducing the healing time of deep burn wounds has always been a major challenge. Traditional dressings not only require a lengthy medical procedure but also cause unbearable pain and secondary damage to patients. In this study, we developed an exudate-absorbing and antimicrobial hydrogel with a curcumin-loaded magnesium polyphenol network (Cur-Mg@PP) to promote burn wound healing. That hydrogel was composed of an ε-poly-l-lysine (ε-PLL)/polymer poly(γ-glutamic acid) (γ-PGA) hydrogel (PP) and curcumin-loaded magnesium polyphenol network (Cur-Mg). Because of the strong water absorption property of ε-PLL and γ-PGA, Cur-Mg@PP powder can quickly absorb the wound exudate and transform into a moist and viscous hydrogel, thus releasing payloads such as magnesium ion (Mg) and curcumin (Cur). The released Mg and Cur demonstrated good therapeutic efficacy on analgesic, antioxidant, anti-inflammation, angiogenesis, and tissue regeneration. Our findings provide a strategy for accelerating burn wound healing.

Enhanced imaging techniques using contrast agents enable high-resolution structural imaging to reveal space-occupying lesions but rarely provide detailed molecular information. To this end, we report a structural and molecular fusion magnetic resonance imaging (MRI) nanoprobe for differential diagnosis between benign and malignant tumors. This fusion nanoprobe, termed FFT NPs, follows a working mechanism involving a -/-weighted magnetic resonance tuning effect (MRET) between a magnetic FeO core and a paramagnetic Fe-tannic acid (Fe-TA) shell. The FFT NPs with an "always-on" inert signal provide structural MRI (sMRI) contrast of tumors while affording an activated signal in the presence of ATP, which is overproduced during the rapid growth of malignant tumors to enable molecular MRI (mMRI) of tumor lesions. We propose the use of the ratiometric mMRI:sMRI intensity to assist in the differential diagnosis of malignant 4T1 tumors from benign L929 fibroblast tumors. Furthermore, the dissociated FFT NPs were found to be able to catalyze HO conversion in 4T1 tumors to generate excess reactive oxygen species (ROS) for chemodynamic therapy. The described fusion nanoprobe strategy enables the differential diagnosis of tumors from a combined spatial and molecular perspective with one-stop MRI imaging with potential applications in precision intervention.

Nanomedicine has revolutionized cancer therapeutic strategies but has not completely changed the outcomes of tricky tumors that evolve a sophisticated immunosuppressive tumor microenvironment (TME) such as acidification. Here, a metal-phenolic network-based nanocomplex embedded with lactate oxidase (LOX) and a mitochondrial respiration inhibitor atovaquone (ATO) was constructed for immunosuppressive TME remodeling and sonodynamic therapy (SDT). In this nanocomplex, the sonosensitizer chlorin e6-conjugated polyphenol derivative can induce the generation of tumor lethal reactive oxygen species upon ultrasound irradiation. LOX served as a catalyst for intracellular lactic acid exhaustion, and ATO led to mitochondrial dysfunction to decrease oxygen consumption. This nanocomplex reversed the tumor immunosuppressive status by alleviating tumor hypoxia and acidic TME, achieving the characteristic enhancement of SDT and the inhibition of tumor proliferation and metastasis.

The immune-excluded tumors (IETs) show limited response to current immunotherapy due to intrinsic and adaptive immune resistance. In this study, it is identified that inhibition of transforming growth factor-β (TGF-β) receptor 1 can relieve tumor fibrosis, thus facilitating the recruitment of tumor-infiltrating T lymphocytes. Subsequently, a nanovesicle is constructed for tumor-specific co-delivery of a TGF-β inhibitor (LY2157299, LY) and the photosensitizer pyropheophorbide a (PPa). The LY-loaded nanovesicles suppress tumor fibrosis to promote intratumoral infiltration of T lymphocytes. Furthermore, PPa chelated with gadolinium ion is capable of fluorescence, photoacoustic and magnetic resonance triple-modal imaging-guided photodynamic therapy, to induce immunogenic death of tumor cells and elicit antitumor immunity in preclinical cancer models in female mice. These nanovesicles are further armored with a lipophilic prodrug of the bromodomain-containing protein 4 inhibitor (i.e., JQ1) to abolish programmed death ligand 1 expression of tumor cells and overcome adaptive immune resistance. This study may pave the way for nanomedicine-based immunotherapy of the IETs.© 2023. The Author(s).

This paper demonstrated for the first time a simple wet-chemical strategy for synthesizing hemin-graphene hybrid nanosheets (H-GNs) through the π-π interactions. Significantly, this new material possesses the advantages of both hemin and graphene and exhibits three interesting properties. First, H-GNs have intrinsic peroxidase-like activity, which can catalyze the reaction of peroxidase substrate, due to the existence of hemin on the graphene surface. Second, their dispersion follow the 2D Schulze-Hardy rule, that is to say, the coagulation of H-GNs in electrolyte solution results from the interplay between van der Waals attraction and electric double-layer repulsion. Third, H-GNs exhibit the ability to differentiate ss- and ds-DNA in optimum electrolyte concentration, owing to the different affinities of ss- and ds-DNA to the H-GNs. On the basis of these unique properties of the as-prepared H-GNs, we have developed a label-free colorimetric detection system for single-nucleotide polymorphisms (SNPs) in disease-associated DNA. To our knowledge, this is the first report concerning on SNPs detection using functionalized graphene nanosheets. Owing to its easy operation and high specificity, it was expected that the proposed procedure might hold great promise in the pathogenic diagnosis and genetic diseases.

Photodynamic therapy (PDT) is a light-triggered therapy used to kill cancer cells by producing reactive oxygen species (ROS). Herein, a new kind of DNA nanostructure based on the coordination between calcium ions (Ca) and AS1411 DNA G quadruplexes to form nanoscale coordination polymers (NCPs) is developed via a simple method. Both chlorine e6 (Ce6), a photosensitizer, and hemin, an iron-containing porphyrin, can be inserted into the G-quadruplex structure in the obtained NCPs. With further polyethylene glycol (PEG) modification, we obtain Ca-AS1411/Ce6/hemin@pHis-PEG (CACH-PEG) NCP nanostructure that enables the intranuclear transport of photosensitizer Ce6 to generate ROS inside cell nuclei that are the most vulnerable to ROS. Meanwhile, the inhibition of antiapoptotic protein B-cell lymphoma 2 (Bcl-2) expression by AS1411 allows for greatly improved PDT-induced cell apoptosis. Furthermore, the catalase-mimicking DNAzyme function of G-quadruplexes and hemin in those NCPs could decompose tumor endogenous HO to in situ generate oxygen so as to further enhance PDT by overcoming the hypoxia-associated resistance. This work develops a simple yet general method with which to fabricate DNA-based NCPs and presents an interesting concept of a nanoscale drug-delivery system that could achieve the intranuclear delivery of photosensitizers, the down-regulation of anti-apoptotic proteins, and the modulation of the unfavorable tumor microenvironment simultaneously for improved cancer therapy.

Breaking the balance of the tumor microenvironment and reshaping it sustainably remain major challenges in lung cancer treatment. Here, a "tumor energy homeostasis disruptor", the CuO@Au nanozyme was developed, which exhibits excellent glucose oxidase-like activity, enabling it to be used for starvation therapy and as a mimic peroxidase for chemodynamic therapy (CDT), producing OH. CuO@Au nanozymes consume glucose at the tumor site to block the tumor's energy supply, produce HO continuously, and lower the pH to enhance the efficiency of CDT, initiating a cascade reaction that leads to a storm of reactive oxygen species (ROS). Furthermore, CuO@Au nanozyme consumes glutathione and reduces the expression of the SLC7A11 (CT) protein to decrease cancer cell uptake of cysteine, further enhancing the burst of ROS, resulting in lipid peroxidation in tumor cells and ultimately leading to ferroptosis. The excellent photothermal performance of CuO@Au can further enhance CDT. Additionally, CuO@Au nanozyme also has computed tomography (CT) and photothermal imaging capabilities. In conclusion, CuO@Au nanozymes, acting as tumor energy homeostasis disruptor, can effectively inhibit tumor growth and successfully achieve the synergistic effects of starvation therapy/CDT/photothermal therapy (PTT). This multifunctional nanozyme holds promise for providing valuable insights and therapeutic strategies for cancer treatment.

Metabolic transformation is a hallmark of cancer and a critical target for cancer therapy. Cancer metabolism and behaviour are regulated by cell-intrinsic factors as well as metabolite availability in the tumour microenvironment (TME). This metabolic niche within the TME is shaped by four tiers of regulation: (1) intrinsic tumour cell metabolism, (2) interactions between cancer cells and non-cancerous cells, (3) tumour location and heterogeneity and (4) whole-body metabolic homeostasis. Here, we define these modes of metabolic regulation and review how distinct cell types contribute to the metabolite composition of the TME. Finally, we connect these insights to understand how each of these tiers offers unique therapeutic potential to modulate the metabolic profile and function of all cells inhabiting the TME.

The nanocatalytic activity of nanozymes provides a vision for tumor treatment. However, the glutathione (GSH)-related antioxidant defense system (ADS) formed on the basis of excessive GSH in the tumor microenvironment limits its catalytic activity. Here, dendritic mesoporous silica nanoparticles (DMSNs) were employed as nanocarrier; ultrasmall FeO nanoparticles, Mn ions, and glutaminase inhibitor Telaglenastat (CB-839) were subsequently integrated into large mesopores of DMSNs, forming DMSN/FeO-Mn@CB-839 (DFMC) nanomedicine. This nanomedicine exhibits peroxidase mimicking activities under acidic conditions, which catalyzes the decomposition of hydrogen peroxide (HO) into hydroxyl radical (OH). This also promotes the formation of lipid peroxides, which is required for ferroptosis. Furthermore, this nanomedicine can effectively deplete the existing GSH, thereby enhancing reactive oxygen species (ROS)-mediated tumor catalytic therapy. Moreover, the introduced CB-839 blocks the endogenous synthesis of GSH, further enhancing GSH depletion performance, which reduces the excretion of oxaliplatin (GSH-related resistance) from tumor cells, thereby restoring the chemical sensitivity of oxaliplatin. The dual GSH depletion property significantly weakens the GSH-related ADS and restores the chemical sensitivity of oxaliplatin, leading to the high DFMC-induced apoptosis and ferroptosis of tumor cells. Our developed nanomedicine based on integrated nanotechnology and clinical drug may aid the development of tumor treatment.

Immune checkpoint blockade (ICB) therapy has attracted widespread attention in cancer treatment. Due to the low immunogenicity and immune suppression state in the tumor microenvironment (TME), the therapeutic effects are only moderate. Herein, a TME-activable manganese-boosted catalytic immunotherapy is designed for synergism with ICB therapy to kill tumors efficiently. The tumor cell membrane (CM)-wrapping multienzyme-mimic manganese oxide (MnO) nanozyme termed CM@Mn showed intrinsic peroxidase and oxidase-like activities in an acidic TME. These activities can generate toxic hydroxyl (OH) and superoxide radicals (O) for tumor cell killing and evoking immunogenic cell death (ICD). Furthermore, the TME-responsive release of Mn directly promotes dendritic cell maturation and macrophage M1 repolarization, resulting in the reversal of an immunosuppressive TME into an immune-activating environment. Additionally, tumor hypoxia relief caused by catalase-like activity also contributes to the process of TME reversal. Finally, a robust tumor-specific T cell-mediated antitumor response occurs with the support of the PD-1 checkpoint blockade. The proliferation of primary and metastatic tumors was inhibited, and a long-term immune memory effect was induced. The therapeutic strategy outlined here may serve as a promising candidate for tumor-integrated treatment.

Deficient catalytic sensitivity to the tumor microenvironment is a major obstacle to nanozyme-mediated tumor therapy. Electron transfer is the intrinsic essence for a nanozyme-catalyzed redox reaction. Here, we developed a nanohole-array-induced metallic molybdenum selenide (MoSe) that is enriched with Se vacancies and can serve as an electronic transfer station for cycling electrons between HO decomposition and glutathione (GSH) depletion. In a MoSe nanohole array, the metallic phase reaches up to 84.5%, which has been experimentally and theoretically demonstrated to exhibit ultrasensitive HO responses and enhanced peroxidase (POD)-like activities for HO thermodynamic heterolysis. More intriguingly, plenty of delocalized electrons appear due to phase- and vacancy-facilitated band structure reconstruction. Combined with the limited characteristic sizes of nanoholes, the surface plasmon resonance effect can be excited, leading to the broad absorption spectrum spanning of MoSe from the visible to near-infrared region (NIR) for photothermal conversion. Under NIR laser irradiation, metallic MoSe is able to induce out-of-balance redox and metabolism homeostasis in the tumor region, thus significantly improving therapeutic effects. This study that takes advantage of phase and defect engineering offers inspiring insights into the development of high-efficiency photothermal nanozymes.