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Transdermal drug delivery system (TDDS) offers lower systemic toxicity and good patient compliance, making it a promising treatment option for skin-related cancers. However, physiological barriers in the skin frequently impede the therapeutic efficiency of TDDS. To address this, a unique self-assembled TDDS that incorporates disulfide pendant groups (termed Sup-TDDS) is presented. It is formulated with dithiolane-containing lipoic acid (LA), photosensitizers Ce6, and chemotherapeutic agents trametinib. Pendant disulfide moieties on Sup-TDDS facilitate thiol-disulfide exchange reactions with exofacial thiols on cell surfaces, thus enhancing stratum corneum penetration. In contrast to intravenous injection, topical administration of Sup-TDDS can penetrate deeper into the skin (> 500 µm) and promote drug accumulation in subcutaneous tumors. In a B16F10-bearing mouse model, Sup-TDDS treatment demonstrates significant anti-tumor effects in primary and recurrent melanoma, benefiting from the synergistic effects of Ce6 and trametinib. These results underscore that Sup-TDDS's transdermal properties allow non-invasive melanoma therapy, implying the potential of nanodrugs containing pendant disulfides for transdermal treatment of skin illnesses., (© 2024 Wiley‐VCH GmbH.)

Malignant tumor has become one of the hellish killers threatening the health of people around the world, its diagnosis and treatment has become the concerns of public. However, the optimal therapeutic dose, undesired side-effect, and long-term immune activation were key and bottleneck problems in tumor treatment. Herein, different batches of supramolecular therapeutic platforms, including vesicles, spherical nanoparticles, and cylindrical nanorods, with precise ratios of dye to drug (1:2) and multiple stimulus responsiveness were constructed by host-guest complexation between cyanine-camptothecin conjugates (IR780-CPT2) and β-cyclodextrin (β-CD) pendent hydrophilic copolymers. The reduction responsiveness, near-infrared photothermal conversion and singlet oxygen ( 1 O 2 ) generation performances endowed these platforms excellent cancer cells killing effect in both of in vitro cellular experiments and in vivo mice models. More importantly, without affecting the weight of mice, the maturation of dendritic cells, proliferation of T cells, up-regulation of high mobility group protein B1, and reduction of immunosuppressive regulatory T cells were detected after employing a synergistic chemo-photo therapy, demonstrating the body's immune effect was successfully activated. Thus, during the treatment of primary tumor, the distal tumor was also inhibited. We believe this work could provide a distinctive way to fabricate supramolecular theranostic platforms with different morphologies and improve antitumor and antimetastasis capabilities., (© 2024 Wiley‐VCH GmbH.)

In wound healing and clinical anti-infection therapy, the current feasibility of nanocatalysts is extremely limited because of inadequate reactive oxygen species (ROS) generation. Herein, a novel H 2 O 2 self-supplying nanocomposite (M/C/AEK) consists of molybdenum disulfide (MoS 2 ) decorated with calcium peroxide (CaO 2 ) prepared at ambient temperature and encapsulated in AEK hydrogel. In the presence of H 2 O 2 and poly(vinyl pyrrolidone) (PVP), CaO 2 nanoclusters, ≈30 nm, are anchored on the MoS 2 surface. MoS 2 /CaO 2 can induce both a cascaded peroxidase (POD)-like and catalase (CAT)-like catalytic activity to produce toxic hydroxyl radicals through self-supplied H 2 O 2 and O 2 responsive to the faintly acidic environment of acute wounds. The POD-like activity is increased under acidic compared with neutral conditions, allowing selective treatment of acute, slightly acidic wounds while avoiding the side effects of high-concentration antibacterial agents on normal tissues. The high near-infrared photothermal effect synergistically with POD-like/CAT-like activity of MoS 2 /CaO 2 boosts the production of more ROS to eradicate Staphylococcus aureus and Escherichia coli bacteria (98.6% and 98.9%) effectively and selectively stimulate wound healing. The porous M/C/AEK hydrogel in the wound microenvironment can efficiently capture bacteria, and its Ca 2+ ions and keratin stimulate healing, revealing excellent potential in advanced wound care and infection control therapies., (© 2024 Wiley‐VCH GmbH.)

Cancer cells support their uncontrolled proliferation primarily by regulating energy metabolism. Inhibiting tumor growth by blocking the supply of nutrients is an effective treatment strategy. Fasting-mimicking diet (FMD), as a low-calorie, low-protein, low-sugar, high-fat diet, can effectively reduce the nutrient supply to tumor cells. However, the significant biological barrier presented by the tumor microenvironment imposes greater demands and challenges for drug design. This study constructs the multifunctional nanocomposite ZnFe 2 O 4 @TiO 2 @CHC@Orl-FA (ZTCOF), which has great potential to overcome the aforementioned drawbacks. ZnFe 2 O 4 @TiO 2 could produce 1 O 2 with ultrasound, and stimulate the Fenton-like conversion of endogenous H 2 O 2 to ·OH, achieving a combined therapeutic effect of sonodynamic therapy (SDT) and chemodynamic therapy (CDT). Orl (Orlistat) and CHC (α-cyano-4-hydroxycinnamic acid) not only block tumor cell energy metabolism but also increase sensitivity to reactive oxygen species, enhancing the cytotoxic effect on tumor cells. Furthermore, combining the treatment strategies with FMD condition control can further inhibit cancer cell energy metabolism, achieving significant synergistic anti-tumor therapy. Both in vitro and in vivo experiments confirm that ZTCOF with SDT/CDT/starvation can achieve effective tumor suppression and destruction. This work provides theoretical and technical support for anti-tumor multimodal synergistic therapy., (© 2024 Wiley‐VCH GmbH.)

Synergistic therapy has become the major therapeutic method for malignant tumors in clinical. Photodynamic therapy (PDT) and radiotherapy (RT) always combine together because of their identical anti-tumor mechanisms, that is reactive oxygen species are generated by the use of radiosensitizers after irradiation by X-ray to efficiently kill cancer cells, PDT also follows similar mechanism. Full exposure of energy-absorbing species in nanomaterials to X-ray or near-infrared light irradiation makes the energy interchange between nanomaterials and surrounding H 2 O or dissolved oxygen easier, however, it remains challenging. Herein, an ultrathin two-dimensional (2D) nanosheet (NS) is developed, Bi 2 O 2 CO 3 , doped with lanthanide ions to give out upconversion luminescence, where the high Z elements Bi, Yb, and Er promote the radio-sensitizing effect. To the surprise, lanthanide activator ions gave out completely different luminescence properties compared with traditional upconversion nanoparticles. Less dopant of Er ions in nanosheets lattice resulted in brighter red emission, which provides more efficient PDT. Under RT/PDT combined treatment, NS shows a good tumor growth-inhibiting effect. In addition, synergistic therapy requires lower radiation dose than conventional radiotherapy and lower light power than single photodynamic therapy, thus greatly reducing radiation damage caused by RT and thermal damage caused by PDT., (© 2024 Wiley‐VCH GmbH.)

Copper is indispensable to organisms, while its homeostatic imbalance may interference normal cellular physiological processes and even induce cell death. Artificially regulating cellular copper content provides a viable strategy to activate antineoplastic effect. In light of this, a copper ions homeostasis perturbator (CuP-CL) with cinnamaldehyde (Cin) packaging and thermosensitive liposome coating is reported. Following laser exposure, the doping of Cu 2+ in polydopamine initiates enhanced photothermal therapy (PTT) and unlocks the outer layer of liposome, leading to the release of copper ions and Cin in tumor microenvironment with mild acidity and high glutathione (GSH) levels. The liberative Cu 2+ can evoke cuproptosis and chemodynamic therapy (CDT). Meanwhile, leveraging the merits of H 2 O 2 supply and GSH consumption, Cin serves as a tumor microenvironment regulator to amplify Cu 2+ mediated cuproptosis and CDT. Additionally, the positive feedback effects of "laser-triggered PTT, PTT accelerates reactive oxygen species (ROS) generation, ROS amplifies lipid peroxide (LPO) accumulation, LPO mediates heat shock proteins (HSPs) clearance, down-regulated HSPs promote PTT" entailed the overall benefit to therapeutic outcomes. Both in vitro and in vivo results corroborate the remarkable antineoplastic performance of CuP-CL by the synergy of cuproptosis/CDT/PTT. Collectively, based on the three-pronged approach, this work plots a viable multimodal regimen for cancer therapy., (© 2024 Wiley‐VCH GmbH.)

Photothermal agents (PTAs) with desirable near-infrared (NIR) absorption and excellent photothermal conversion efficiency (PCE) are ideal candidates for cancer treatment. However, numerous PTAs still require high-intensity and long-duration laser irradiation to completely ablate the tumor during the photothermal therapy (PTT) process, resulting in light damage to healthy skin and tissue as well as limiting their biomedical applications. Integrating intense NIR absorption and high PCE into a single small-molecule PTA is an important prerequisite for realizing efficient PTT, but is a serious challenge. Herein, a series of donor-acceptor type PTAs (CC1 to NC4) are designed through a molecular engineering strategy. Theoretical calculations and experimental results show that the NIR absorption and photothermal effect from CC1 to NC4 are significantly enhanced as expected. Notably, NC4 nanoparticles exhibit intense NIR absorption, superhigh PCE of up to 88.9% for PTT, photoacoustic imaging and photothermal imaging, and effective reactive oxygen species generation for photodynamic therapy (PDT). The superior PTT/PDT synergistic phototherapeutic efficacy is well demonstrated by the complete elimination of tumor in vivo upon one-time, low-intensity, and short-duration laser irradiation (808 nm, 330 mW cm -2 , and 3 min). This work provides a valuable guideline for rational design of PTAs for cancer phototherapy., (© 2024 Wiley‐VCH GmbH.)

Postoperative tumor recurrence and wound infection remain significant clinical challenges in surgery, often requiring adjuvant therapies. The combination treatment of photothermal therapy (PTT) and chemodynamic therapy (CDT) has proven to be effective in cancer treatment and wound infection. However, the hyperthermia during PTT increases the risk of normal tissue damage, severely impeding its application. Moreover, the efficacy of CDT is limited by insufficient hydrogen peroxide (H 2 O 2 ) and excessive glutathione (GSH) levels at tumor or infection sites. Herein, an injectable and multifunctional CuO 2 @Au hydrogel system (CuO 2 @Au Gel) is developed for synergistic CDT and low-temperature PTT (LTPTT) to prevent tumor recurrence and bacterial wound infections. CuO 2 @Au Gel is constructed by embedding therapeutic CuO 2 @Au into low-melting point agarose hydrogel. In vitro and in vivo experiments confirm that the CuO 2 @Au in CuO 2 @Au Gel is capable of self-supplying H 2 O 2 and depleting GSH, exhibiting effective CDT effect in acidic tumor or bacterial infected microenvironment. Additionally, it exhibits favorable photothermal conversion ability, inducing localized temperature elevation and synergistically enhancing CDT efficiency. The prepared CuO 2 @Au Gel demonstrates efficient tumor ablation capability in post-surgery recurrence mouse models and exhibits promising anti-infective efficiency in bacterial infection wound models, indicating significant potential in adjuvant therapy for post-surgical treatment and recovery., (© 2024 Wiley‐VCH GmbH.)

The development of nanoassemblies, activated by the tumor microenvironment, capable of generating photothermal therapy (PTT) and amplifying the "ROS (·OH) storm," is essential for precise and effective synergistic tumor treatment. Herein, an innovative cascade-amplified nanotheranostics based on biodegradable Pd-BSA-GOx nanocomposite for NIR-II photoacoustic imaging (PAI) guides self-enhanced NIR-II PTT/chemodynamic therapy (CDT)/starvation synergistic therapy. The Pd-BSA-GOx demonstrates the ability to selectively convert overexpressed H 2 O 2 into strongly toxic ·OH by a Pd/Pd 2+ -mediated Fenton-like reaction at a lower pH level. Simultaneously, the GOx generates H 2 O 2 and gluconic acid, effectively disrupting nutrient supply and instigating tumor starvation therapy. More importantly, the heightened levels of H 2 O 2 and increased acidity greatly enhance the Fenton-like reactivity, generating a significant "·OH storm," thereby achieving Pd 2+ -mediated cascade-amplifying CDT. The specific PTT facilitated by undegraded Pd accelerates the Fenton-like reaction, establishing a positive feedback process for self-enhancing synergetic PTT/CDT/starvation therapy via the NIR-II guided-PAI. Therefore, the multifunctional nanotheranostics presents a simple and versatile strategy for the precision diagnosis and treatment of tumors., (© 2024 Wiley‐VCH GmbH.)

Chemodynamic therapy (CDT) is a particular oncological therapeutic strategy by generates the highly toxic hydroxyl radical (•OH) from the dismutation of endogenous hydrogen peroxide (H 2 O 2 ) via Fenton or Fenton-like reactions. However, single CDT therapies have been limited by unsatisfactory efficacy. Enhanced chemodynamic therapy (ECDT) triggered by near-infrared (NIR) is a novel therapeutic modality based on light energy to improve the efficiency of Fenton or Fenton-like reactions. However, the limited penetration and imaging capability of the visible (400-650 nm) and traditional NIR-I region (650-900 nm) light-amplified CDT restrict the prospects for its clinical application. Combined with the high penetration/high precision imaging characteristics of the second near-infrared (NIR-II,) nanoplatform, it is expected to kill deep tumors efficiently while imaging the treatment process in real-time, and more notably, the NIR-II region radiation with wavelengths above 1000 nm can minimize the irradiation damage to normal tissues. Such NIR-II ECDT nanoplatforms have greatly improved the effectiveness of CDT therapy and demonstrated extraordinary potential for clinical applications. Accordingly, various strategies have been explored in the past years to improve the efficiency of NIR-II Enhanced CDT. In this review, the mechanisms and strategies used to improve the performance of NIR-II-enhanced CDT are outlined., (© 2023 Wiley‐VCH GmbH.)

Photodynamic therapy (PDT) with aggregation-induced emission (AIE) photosensitizers (PSs) is a promising therapeutic strategy to achieve better anticancer results. However, eradicating solid tumors completely by PDT alone can be difficult owing to the inherent drawbacks of this treatment, and the combination of PDT with other therapeutic modalities provides opportunities to achieve cooperative enhancement interactions among various treatments. Herein, this work presents the construction of a biocompatible nanocomposite, namely CaO 2 @DOX@ZIF@ASQ, featuring light-responsive reactive oxygen species (ROS) generation and tumor-targeting oxygen and hydrogen peroxide discharge, as well as controlled doxorubicin (DOX) and copper ion release, thus allowing the combined PDT/CT/CDT effect by AIE PS-enhanced PDT, DOX-based chemotherapy (CT), and copper-involved Fenton-like reaction-driven chemodynamic therapy (CDT). In vitro and in vivo studies verify that the generation of both ROS and O 2 by this nanomedicine, stimulated by light, exhibits superior anticancer efficacy, alleviating tumor hypoxia and achieving synergistic PDT/CT/CDT therapeutic effect. This multifunctional nanomedicine remarkably suppresses the tumor growth with minimized systemic toxicity, providing a new strategy for constructing multimodal PDT/CT/CDT therapeutic systems to overcome hypoxia limitations, and potentially increase the antitumor efficacy at lower doses of PSs and chemotherapeutic drugs, thus minimizing potential toxicity to non-malignant tissues., (© 2023 Wiley‐VCH GmbH.)

Cancer is one of the most serious diseases challenging human health and life span. Cancer has claimed millions of lives worldwide. Early diagnosis and effective treatment of cancer are very important for the survival of patients. In recent years, 2D nanomaterials have shown great potential in the development of anticancer treatment by combining their inherent physicochemical properties after surface modification. 2D nanomaterials have attracted great interest due to their unique nanosheet structure, large surface area, and extraordinary physicochemical properties. This article reviews the advantages and application status of emerging 2D nanomaterials for targeted tumor synergistic therapy compared with traditional therapeutic strategies. In order to investigate novel potential anticancer strategies, this paper focuses on the surface modification, cargo delivery capability, and unique optical properties of emerging 2D nanomaterials. Finally, the current problems and challenges in cancer treatment are summarized and prospected., (© 2023 Wiley-VCH GmbH.)

Due to the limitations of H 2 O 2 under physiological conditions and defective activity, nanozyme-catalyzed therapy for infected diabetic wound healing is still a huge challenge. Here, this work designs a novel multifunctional hybrid glucose oxidase (GOx)-CeO 2 @black phosphorus (BP)/Apt nanosheet that features GOx and CeO 2 dual enzyme loading with photothermal enhancement effect and targeting ability for the treatment of infected wounds in type II diabetic mice. Combined with the photothermal properties of the BP nanosheets, the cascade nanozyme effect of GOx and CeO 2 is extremely enhanced. The synergistic effect of peroxidase activity and photothermal therapy with targeting aptamer allows for overcoming the catalytic defects of nanozyme and significantly improving in vitro bacterial inhibition rate with 99.9% and 97.8% for Staphylococcus aureus and Escherichia coli, respectively, as well as enhancing in vivo antibacterial performance with the lowest wound remained (0.05%), reduction of infiltration inflammatory cells, and excellent biocompatibility. Overall, this work builds a nanodelivery system with a powerful therapeutic approach, incorporating self-supplying H 2 O 2 synergistic photothermal and real-time wound monitoring effect, which holds profound potential as a clinical treatment for infected diabetic wounds., (© 2023 Wiley-VCH GmbH.)

Hypoxia is an important feature, which can upregulate the hypoxia-inducible factor-1α (HIF-1α) expression and promote the activation of hepatic stellate cells (HSCs), leading to liver fibrosis. Currently, effective treatment for liver fibrosis is extremely lacking. Herein, a safe and effective method is established to downregulate the expression of HIF-1α in HSCs via targeted delivery of VA-PEG-modified CNs-based nanosheets-encapsulated (VA-PEG-CN@GQDs) HIF-1α small interfering RNA (HIF-1α-siRNA). Due to the presence of lipase in the liver, the reversible release of siRNA can be promoted to complete the transfection process. Simultaneously, VA-PEG-CN@GQD nanosheets enable trigger the water splitting process to produce O 2 under near-infrared (NIR) irradiation, thereby improving the hypoxic environment of the liver fibrosis site and maximizing the downregulation of HIF-1α expression to improve the therapeutic effect, as demonstrated in liver fibrosis mice. Such combination therapy can inhibit the activation of HSCs via HIF-1α-mediated TGF-β1/Smad pathway, achieving outstanding therapeutic effects in liver fibrosis mice. In conclusion, this study proposes a novel strategy for the treatment of liver fibrosis by regulating the hypoxic environment and the expression of HIF-1α at lesion site., (© 2023 Wiley-VCH GmbH.)

Accurate location and efficient treatment of diseases by multifunctional nanoplatforms are appealing but face great challenges. Theranostic agents through the physical combination of different functional nanoparticles are demonstrated to be effective. Yet, the complicated biological environment often leads to ambiguous fates of each agent, which fails to keep the behaviors of imaging and therapeutic components in a simultaneous manner. Herein, "integrated" theranostic NPs, Gd-doped CuWO 4 (CWG) with strong near-infrared (808 nm) absorption, the longest absorption peak of reported CuWO 4 , located in the biological transparent window, are constructed. The single doping of trace amount of Gd not only endows them with a distinguished magnetic resonance imaging capability (r 1 = 12.01 mM -1 s -1 ), but also concurrently imposes great effect on the valence states of matrix ion (Cu), as evidenced by theoretical calculation results. The charge distribution shift of Cu would facilitate ·OH generation, beneficial for chemodynamic therapy (CDT). Moreover, CWG NPs display remarkable photoacoustic (PA) and computed tomography (CT) imaging capabilities (S = 10.33 HU mM -1 ). Such integrated theranostics afford a paradigm for multimodal imaging-guided synergistic therapy with all-in-one single nanoparticle., (© 2023 Wiley-VCH GmbH.)

The combination of chemo/chemodynamic therapy is a promising strategy for improving antitumor efficacy. Herein, metal-phenolic network nanoparticles (NPs) self-assembled from copper ions and gallic acid (Cu-GA) are developed to evoke apoptosis and cuproptosis for synergistic chemo/chemodynamic therapy. The Cu-GA NPs are biodegraded in response to the highly expressed glutathione (GSH) in tumor cells, resulting in the simultaneous release of Cu + and GA. The intracellular GSH content is dramatically reduced by the released GA, rendering the tumor cells incapable of scavenging reactive oxygen species (ROS) and more susceptible to cuproptosis. Meanwhile, ROS levels within the tumor cells are significantly increased by the Fenton-like reaction of released Cu + , which disrupts redox homeostasis and achieves apoptosis-related chemodynamic therapy. Moreover, massive accumulation of Cu + in the tumor cells further induces aggregation of lipoylated dihydrolipoamide S-acetyltransferase and downregulation of iron-sulfur cluster protein, activating cuproptosis to enhance the antitumor efficacy of Cu-GA NPs. The experiments in vivo further demonstrate that Cu-GA NPs exhibited the excellent biosafety and superior antitumor capacity, which can efficiently inhibit the growth of tumors due to the activation by the tumor specific GSH and hydrogen peroxide. These Cu-based metal-phenolic network NPs provide a potential strategy to build up efficient and safe cancer therapy., (© 2023 Wiley-VCH GmbH.)

Critical limb ischemia, the final course of peripheral artery disease, is characterized by an insufficient supply of blood flow and excessive oxidative stress. H 2 S molecular therapy possesses huge potential for accelerating revascularization and scavenging intracellular reactive oxygen species (ROS). Moreover, it is found that BMP6 is the most significantly up-expressed secreted protein-related gene in HUVECs treated with GYY4137, a H 2 S donor, based on the transcriptome analysis. Herein, a UIO-66-NH 2 @GYY4137@BMP6 co-delivery nanoplatform to strengthen the therapeutic effects of limb ischemia is developed. The established UIO-66-NH 2 @GYY4137@BMP6 nanoplatform exerts its proangiogenic and anti-oxidation functions by regulating key pathways. The underlying molecular mechanisms of UIO-66-NH 2 @GYY4137@BMP6 dual-loading system lie in the upregulation of phosphorylated YAP/TAZ and Jun to promote HUVECs proliferation and downregulation of phosphorylated p53/p21 to scavenge excessive ROS. Meanwhile, laser-doppler perfusion imaging (LDPI), injury severity evaluation, and histological analysis confirm the excellent therapeutic effects of UIO-66-NH 2 @GYY4137@BMP6 in vivo. This work may shed light on the treatment of critical limb ischemia by regulating YAP, Jun, and p53 signaling pathways based on gas-protein synergistic therapy., (© 2023 Wiley-VCH GmbH.)

To strengthen the antitumor efficacy and avoid toxicity to normal cells of cisplatin and triptolide, herein, an acid and glutathione (GSH) dual-controlled nanoplatform for enhanced cancer treatment through the synergy of both "1+1" apoptosis and "1+1" ferroptosis is designed. Remarkably, ZIF8 in response to tumor microenvironment enhances drug targeting and protects drugs from premature degradation. Meanwhile, the Pt IV  center can be easily reduced to cisplatin because of the large amount of GSH, thus liberating the triptolide as the coordinated ligand. The released cisplatin and hemin in turn boost the tumor cell "1+1" apoptosis through chemotherapy and photodynamic therapy, respectively. Furthermore, GSH reduction through Pt IV  weakens the activation of glutathione peroxidase 4 (GPX4) effectively. The released triptolide can inhibit the expressions of GSH by regulating nuclear factor E2 related factor 2 (Nrf2), further promoting membrane lipid peroxidation, thus "1+1" ferroptosis can be achieved. Both in vitro and in vivo results demonstrate that the nanosystem can not only perform superior specificity and therapeutic outcomes but also reduce the toxicity to normal cells/tissues of cisplatin and triptolide effectively. Overall, the prodrug-based smart system provides an efficient therapeutic strategy for cancer treatment by virtue of the effect of enhanced "1+1" apoptosis and "1+1" ferroptosis therapies., (© 2023 Wiley-VCH GmbH.)

Cuproptosis, a kind of newly recognized cell death modality, shows enormous prospect in cancer treatment. The inducer of cuproptosis has more advantages in tumor therapy, especially that can trigger cuproptosis and chemodynamic therapy (CDT) simultaneously. However, cuproptosis is restricted to the deficiency of intracellular copper ions and the nonspecific delivery of copper-based ionophores. Therefore, high level delivery, responsive release, and utilizing synergistic-function of inducer become the key on cuproptosis-based oncotherapy. In this work, a cascade nanosystem is constructed for enhanced cuproptosis and CDT. In the weak acidic environment of tumor cells, DNA, zinc ions, and Cu + can release from the nanosystem. Since Cu + having superior performance in mediating both Fenton-like reaction and cuproptosis, the released Cu + induces cuproptosis and CDT efficiently, accompanied by Cu 2+ generation. Then Cu 2+ can be converted into Cu + partially by glutathione (GSH) to from a Cu + supply loop and ensure the synergistic action. Meanwhile, the consumption of GSH also contributes to cuproptosis and CDT in return. Finally, DNA and Zn 2+ form DNAzyme to shear catalase-related RNA, resulting in the accumulation of hydrogen peroxide and further enhancing combination therapy. These results provide a promising nanotherapeutic platform and may inspire the design for potential cancer treatment based on cuproptosis., (© 2023 Wiley-VCH GmbH.)

The fast renal clearance of hydrophilic small molecular anticancer drugs and ultrasmall nanoparticles (NPs) results in the low utilization rate and certain side effects, thus improving the tumor targeting is highly desired but faces great challenges. A novel and general β-cyclodextrin (CD) aggregation-induced assembly strategy to fabricate doxorubicin (DOX) and CD-coated NPs (such as Au) co-encapsulated pH-responsive nanocomposites (NCs) is proposed. By adding DOX×HCl and reducing pH in a reversed microemulsion system, hydrophilic CD-coated AuNPs rapidly assemble into large NCs. Then in situ polymerization of dopamine and sequentially coordinating with Cu 2+ on the surface of NCs provide extra weak acid responsiveness, chemodynamic therapy (CDT), and improved biocompatibility as well as stability. The subsequent tumor microenvironment responsive dissociation notably improves their passive tumor targeting, bioavailability, imaging, and therapeutic capabilities, as well as facilitates their internalization by tumor cells and metabolic clearance, thereby reducing side effects. The combination of polymerized dopamine and assembled AuNPs reinforces photothermal capability, thus further boosting CDT through thermally amplifying Cu-catalyzed Fenton-like reaction. Both in vitro and in vivo studies confirm the desirable outcomes of these NCs as photoacoustic imaging guided trimodal (thermally enhanced CDT, photothermal therapy, and chemotherapy) synergistic tumor treatment agents with minimal systemic toxicity., (© 2023 Wiley-VCH GmbH.)

Ferroptosis is identified as a novel type of cell death with distinct properties involved in physical conditions and various diseases, including cancers. It is considered that ferroptosis provides a promising therapeutic strategy for optimizing oncotherapy. Although erastin is an effective ferroptosis trigger, the potential of its clinical application is largely restricted by its poor water solubility and concomitant limitations. To address this issue, an innovative nanoplatform (PE@PTGA) that integrated protoporphyrin IX (PpIX) and erastin coated with amphiphilic polymers (PTGA) to evoke ferroptosis and apoptosis is constructed and exemplified using an orthotopic hepatocellular carcinoma (HCC) xenograft mouse model as a paradigm. The self-assembled nanoparticles can enter HCC cells and release PpIX and erastin. With light stimulation, PpIX exerts hyperthermia and reactive oxygen species to inhibit the proliferation of HCC cells. Besides, the accumulated reactive oxygen species (ROS) can further promote erastin-induced ferroptosis in HCC cells. In vitro and in vivo studies reveal that PE@PTGA synergistically inhibits tumor development by stimulating both ferroptosis- and apoptosis-related pathways. Moreover, PE@PTGA has low toxicity and satisfactory biocompatibility, suggesting its promising clinical benefit in cancer treatments., (© 2023 Wiley-VCH GmbH.)

To overcome the limitations of doxorubicin (DOX) chemotherapy, nanomedicines that integrate additional photothermal therapy (PTT) and chemodynamic therapy (CDT) strategies are highlighted as promising alternatives for the treatment of malignant tumors. However, time-consuming preparation processes, biosafety concerns, and the bottlenecks of individual therapeutic modalities often limit the practical applications of this strategy. To address these issues, this work designs an oxygen economizer that additionally serves as a Fenton reaction amplifier through the simple assembly of epigallocatechin gallate (EGCG), pluronic F-127 (PF127), iron (III) ions, and doxorubicin (DOX) for the enhancement of synergistic PTT/CDT/chemotherapy. The resulting nanoformulation, EFPD, can target mitochondria and inhibit cell respiration to reduce O 2 consumption, thus boosting DOX-mediated H 2 O 2 generation for enhanced CDT and simultaneously improving hypoxia-limited DOX chemotherapy efficacy. Moreover, the coordination between EGCG and Fe 3+ provides EFPD with excellent photothermal conversion efficiencies (η = 34.7%) for PTT and photothermal-accelerated drug release. Experimental results indicate that EFPD-mediated synergistic enhancement of PTT/CDT/chemotherapy can achieve excellent therapeutic outcomes, including enhanced ablation of solid tumors, reduced metastasis and cardiotoxicity, and extended life spans., (© 2023 Wiley-VCH GmbH.)

Hypercoagulation threatens the lives of cancer patients and cancer progression. Platelet overactivation attributes to the tumor-associated hypercoagulation and maintenance of the tumor endothelial integrity, leading to limited intratumoral perfusion of nanoagents into solid tumors in spite of the enhanced penetration and retention effect (EPR). Therefore, the clinical application of nanotherapeutics in solid cancer still faces great challenges. Herein, this work establishes platelet inhibiting nanoagents based on Fe III -doped C 3 N 4 coloaded with the chemotherapy drug and the antiplatelet drug chlorogenic acid (CA), further opening tumor vascular endothelial junctions, thereby disrupting the tumor vascular endothelial integrity, and enhancing drug perfusion. Moreover, CA not only damages the cancer cells but also potentiates the cytotoxicity induced by the chemotherapy drug doxorubicin, synergistically ablating the tumor tissue. Further, the introduction of CA relieves the original causes of the hypercoagulable state such as tissue factor (TF), thrombin, and matrix metalloproteinases (MMPs) secreted by cancer cells. It is anticipated that the hypercoagulation- and platelet-inhibition strategy by integration of phenolic acid CA into chemotherapy provides insights into platelet inhibition-assisted theranostics based on nanomedicines., (© 2022 Wiley-VCH GmbH.)

Ferroptosis, characterized by the accumulation of reactive oxygen species and lipid peroxides, has emerged as an attractive strategy to reverse drug resistance. Of particular interest is the ferroptosis-apoptosis combination therapy for cancer treatment. Herein, a nanoplatform is reported for effective co-delivery of the anticancer drug sorafenib (S) and the ferroptosis inducer hemin (H), toward synergistic ferroptosis-apoptosis therapy of advanced hepatocellular carcinoma (HCC) as a proof-of-concept study. Liposome is an excellent delivery system; however, it is not sufficiently responsive to the acidic tumor microenvironment (TME) for tumor-targeted drug delivery. The pH-sensitive vesicles are therefore developed (SH-AD-L) by incorporating amphiphilic dendrimers (AD) into liposomes for controlled and pH-stimulated release of sorafenib and hemin in the acidic TME, thanks to the protonation of numerous amine functionalities in AD. Importantly, SH-AD-L not only blocked glutathione synthesis to disrupt the antioxidant system, but also increased intracellular Fe 2+ and ·OH concentrations to amplify oxidative stress, both of which contribute to enhanced ferroptosis. Remarkably, high levels of ·OH also augmented sorafenib-mediated apoptosis in tumor cells. This study demonstrates the efficacy of ferroptosis-apoptosis combination therapy, as well as the promise of the AD-doped TME-responsive vesicles for drug delivery in combination therapy to treat advanced HCC., (© 2023 Wiley-VCH GmbH.)

Adoptive cell therapy by natural cells for drug delivery has achieved encouraging progress in cancer treatment over small-molecule drugs. Macrophages have a great potential in antitumor drug delivery due to their innate capability of sensing chemotactic cues and homing toward tumors. However, major challenge in current macrophage-based cell therapy is loading macrophages with adequate amounts of therapeutic, while allowing them to play a role in immunity without compromising cell functions. Herein, a potent strategy to construct a macrophage-mediated drug delivery platform loaded with a nanosphere (CpG-ASO-Pt) (CAP) composed of functional nucleic acid therapeutic (CpG-ASO) and chemotherapeutic drug cisplatin (Pt) is demonstrated. These CAP nanosphere loaded macrophages (CAP@M) are employed not only as carriers to deliver this nanosphere toward the tumor sites, but also simultaneously to guide the differentiation and maintain immunostimulatory effects. Both in vitro and in vivo experiments indicate that CAP@M is a promising nanomedicine by macrophage-mediated nanospheres delivery and synergistically immunostimulatory activities. Taken together, this study provides a new strategy to construct a macrophage-based drug delivery system for synergistic chemo-/gene-/immuno-therapy., (© 2022 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Traditional cancer therapy is limited by poor prognosis and risk of recurrence. Emerging therapies offer alternatives to these problems. In addition, synergistic therapy can combine the advantages of multiple therapies to eliminate cancer cells while attenuating damage to normal tissues. Herein, a theranostic nanoplatform based on the chemotherapeutic drug mitoxantrone (MTO) and glucose oxidase (GOx) co-loaded γ-Fe 2 O 3 nanoparticles (MTO-GOx@γ-Fe 2 O 3 NPs) is designed and prepared to realize photoacoustic imaging-guided chemo/chemodynamic/photothermal (CT/CDT/PTT) synergistic cancer therapy. With a particle size of about 86.2 nm, the synthesized MTO-GOx@γ-Fe 2 O 3 NPs can selectively accumulate at tumor sites by enhanced permeability and retention (EPR) effects. After entering cancer cells by endocytosis, MTO-GOx@γ-Fe 2 O 3 NPs decompose into Fe 3+ ions and release cargo because of their pH-responsive characteristic. As a Food and Drug Administration (FDA)-approved chemotherapy drug, MTO shows strong DNA disruption ability and satisfying photothermal conversion ability under laser irradiation for photothermal therapy. Simultaneously, GOx catalyzes the decomposition of glucose and generates hydrogen peroxide (H 2 O 2 ) to enhance the chemodynamic therapy efficiency. In vitro and in vivo experiments reveal that MTO-GOx@γ-Fe 2 O 3 NPs possess a significant synergistic therapeutic effect in cancer treatment., (© 2022 Wiley-VCH GmbH.)

Sonodynamic therapy is a noninvasive treatment method that generates reactive oxygen species (ROS) triggered by ultrasound, to achieve oxidative damage to tumors. However, methods are required to improve the efficiency of ROS generation and achieve continuous oxidative damage. A ternary heterojunction sonosensitizer composed of Bi@BiO 2- x @Bi 2 S 3 -PEG (BOS) to achieve thermal injury-assisted continuous sonodynamic therapy for tumors is prepared. The oxygen vacancy in BOS can capture hot electrons and promotes the separation of hot carriers on the bismuth surface. The local electric field induced by localized surface plasmon resonance also contributes to the rapid transfer of electrons. Therefore, BOS not only possesses the functions of each component but also exhibits higher catalytic activity to generate ROS. Meanwhile, BOS continuously consumes glutathione, which is conducive to its biodegradation and achieves continuous oxidative stress injury. In addition, the photothermal conversion of BOS under near-infrared irradiation helps to achieve thermal tumor damage and further relieves tumor hypoxia, thus amplifying the sonodynamic therapeutic efficacy. This process not only provides a strategy for thermal damage to amplify the efficacy of sonodynamic therapy, but also expands the application of bismuth-based heterojunction nanomaterials as sonosensitizers in sonodynamic therapy., (© 2022 Wiley-VCH GmbH.)

Gas therapy is an emerging "green" cancer treatment strategy; however, its outcome often restricted by the complexity, diversity, and heterogeneity of tumor. Herein, a tumor targeting and tumor microenvironment-activated calcium phosphate nanotheranostic system (denoted as GCAH) is constructed for effective synergistic cancer starvation/gas therapy. GCAH is obtained by a facile biomineralization strategy using glucose oxidase (GOx) as a biotemplate, followed by loading of l-Arginine (L-Arg) and modification of hyaluronic acid (HA) to allow special selectivity for glycoprotien CD44 overexpressed cancer cells. This nanotheranostic system not only exhausts the glucose nutrients in tumor region by the GOx-triggered glucose oxidation, the generated H 2 O 2 can oxidize L-Arg into NO under acidic tumor microenvironment for enhanced gas therapy. As such, there are significant enhancement effects of starvation therapy and gas therapy through the cascade reactions of GOx and L-Arg, which yields a remarkable synergistic therapeutic effect for 4T1 tumor-bearing mice without discernible toxic side effects., (© 2021 Wiley-VCH GmbH.)

Theranostic prodrugs that can precisely monitor drug activation with synergistic therapeutic effects are highly desirable for personalized medicine. In this study, a theranostic heterodimeric prodrug, CyNH-SS-DOX, with synchronous and independent dual-channel fluorescence turn-on and dual-prodrug activation for synergistic cancer therapy is developed. A hemicyanine fluorescent drug, CyNH 2 , with good therapeutic effects found in this work, is conjugated to doxorubicin (DOX) through a disulfide linker to form CyNH-SS-DOX. Before activation, both the fluorescence of DOX and CyNH 2 are in the off state and the toxicity is low. In the presence of intracellular glutathione, both the fluorescence of DOX and CyNH 2 at different channels are turned on. Meanwhile, DOX and CyNH 2 are activated in a synergistic anticancer effect. It is believed that CyNH-SS-DOX is promising for monitoring prodrug activation in dual-fluorescence channels and for enhancing therapeutic efficacy with few side effects., (© 2021 Wiley-VCH GmbH.)

Utilizing catalase-mimicking nanozymes to produce O 2 is an effective method to overcome tumor hypoxia. However, it is challenging to fabricate nanozymes with ultrahigh catalytic activity. Palladium nanosheet (Pd NS), a photothermal agent for photothermal therapy (PTT), has superior catalase-mimicking activity. Here, titanium dioxide (TiO 2 ) is used to modify Pd NS (denoted Pd@TiO 2 ) by a simple one-step method to improve its catalytic activity about 8 times. The enhancement mechanism's fundamental insights are discussed through experiments and density functional theory calculations. Next, zinc phthalocyanine is loaded on Pd@TiO 2 to form a nanomotor (denoted PTZCs) with the synergistic activities of photodynamic therapy and PTT. PTZCs inherit the catalase activity of Pd@TiO 2 to facilitate the decomposition of endogenous H 2 O 2 to O 2 , which can relieve tumor hypoxia and propel PTZC migration to expand the reach of PTZCs, further enhancing its synergistic treatment outcome both in vitro and in vivo. It is proposed that this work can provide a simple and effective strategy for catalytic activity enhancement and bring a critical new perspective to studying and guiding the nanozyme design., (© 2021 Wiley-VCH GmbH.)

The strategies of combining photodynamic therapy (PDT) with other therapeutics are considered to be the most suitable methods in improving the antitumor therapeutic efficiency. Herein, a "Linkage Mechanism" strategy based on thermal controllable multishell nanoparticles (CuS@SiO 2 -l-Arg (l-arginine)@PCM (phase-change material)-Ce6 (chiorin e6)) is proposed for combing PDT and NO-based gas therapy. Upon 1060 nm laser irradiation, the PCMs will melt under the photothermal effect induced by CuS and the loaded Ce6 and l-Arg can accurately release from the nanoparticles. Under further 660 nm laser irradiation, the released Ce6 will produce plenty of singlet oxygen ( 1 O 2 ) for PDT, while the generated 1 O 2 can oxidize l-Arg to release NO for the synergy of PDT and gas therapy. The "Linkage Mechanism" can achieve precise release of the payloads under the control of photothermal effect at tumor site, and the chain reaction of PDT and gas therapy overcomes the problem of premature release of gas during transportation. Benefiting from the guidance of fluorescence imaging and second near infrared photoacoustic imaging by Ce6 and CuS, both in vitro and in vivo experiments present effective antitumor efficiencies. The nanoparticles provide new ideas for controllable release of drugs and the synergistic effect of multiple treatments, possessing great application prospects., (© 2021 Wiley-VCH GmbH.)

Immune checkpoint blockade therapy (ICBT) targeting checkpoints, such as, cytotoxic T-lymphocyte associated protein-4 (CTLA-4), programmed death-1 (PD-1), or programmed death-ligand 1 (PD-L1), can yield durable immune response in various types of cancers and has gained constantly increasing research interests in recent years. However, the efficacy of ICBT alone is limited by low response rate and immune-related side effects. Emerging preclinical and clinical studies reveal that chemotherapy, radiotherapy, phototherapy, or other immunotherapies can reprogramm immunologically "cold" tumor microenvironment into a "hot" one, thus synergizing with ICBT. In this review, the working principle and current development of various immune checkpoint inhibitors are summarized, while the interactive mechanism and recent progress of ICBT-based synergistic therapies with other immunotherapy, chemotherapy, phototherapy, and radiotherapy in fundamental and clinical studies in the past 5 years are depicted and highlighted. Moreover, the potential issues in current studies of ICBT-based synergistic therapies and future perspectives are also discussed., (© 2021 Wiley-VCH GmbH.)

Hepatocellular carcinoma (HCC) is one of the most common and deadliest malignancy cancers, which remains a major global health problem. At present, over 50% of patients with HCC have implemented systemic therapies, such as interventional therapy or local chemotherapy that are scarcely effective and induce serious side effects to the remaining normal liver, further limiting their clinical outcomes. Herein, a tumor microenvironment triggered cascade-activation nanoplatform (A-NP Lap/TPZ ) is prepared based on β-lapachone (β-Lap) and tirapazamine (TPZ) for the synergistic therapy of HCC. The A-NP Lap/TPZ exerts its targeting effect by binding to the receptor of tumor cells with an external aptamer. In the tumor microenvironment, the nanoplatform can realize H 2 O 2 -triggered disassembly to release β-Lap and TPZ. The released β-Lap generates ROS to induce tumor cell apoptosis under the catalysis of the tumor cell over-expressed NAD(P)H-quinone oxidoreductase-1 (NQO1) enzyme. In this process, oxygen is consumed to intensify tumor hypoxia, and eventually cascade activates TPZ to exert the anti-tumor effect. The studies in vitro and in vivo consistently demonstrate that the as-prepared A-NP Lap/TPZ nanoplatform possesses an excellent synergistic anti-tumor effect. This design of nanoplatform with cascade activation effect provides a promising strategy for HCC treatment., (© 2021 Wiley-VCH GmbH.)

Cancer immunotherapy is a new therapeutic strategy to fight cancer by activating the patients' own immune system. At present, immunotherapy approaches such as cancer vaccines, immune checkpoint blockade (ICB), adoptive cell transfer (ACT), monoclonal antibodies (mAbs) therapy, and cytokines therapy have therapeutic potential in preclinical and clinical applications. However, the intrinsic limitations of conventional immunotherapy are difficulty of precise dosage control, insufficient enrichment in tumor tissues, partial immune response silencing or hyperactivity, and high cost. Engineering nanoparticles (NPs) have been emerging as a promising multifunctional platform to enhance conventional immunotherapy due to their intrinsic immunogenicity, convenient delivery function, controlled surface chemistry activity, multifunctional modifying potential, and intelligent targeting. This review presents the recent progress reflected by engineering NPs, including the diversified selection of functionalized NPs, the superiority of engineering NPs for enhancing conventional immunotherapy, and NP-mediated multiscale strategies for synergistic therapy consisting of compositions and their mechanism. Finally, the perspective on multifunctional NP-based cancer immunotherapy for boosting immunomodulation is discussed, which reveals the expanding landscape of engineering NPs in clinical translation., (© 2020 Wiley-VCH GmbH.)

Bimetallic nanoparticles have received considerable attention owing to synergistic effect and their multifunctionality. Herein, new multifunctional Pd@Au bimetallic nanoplates decorated hollow mesoporous MnO 2 nanoplates (H-MnO 2 ) are demonstrated for achieving not only nucleus-targeted NIR-II photothermal therapy (PTT), but also tumor microenvironment (TME) hypoxia relief enhanced photodynamic therapy (PDT). The Pd@Au nanoplates present a photothermal conversion efficiency (PTCE) as high as 56.9%, superior to those PTAs activated in the NIR-II region such as Cu 9 S 5 nanoparticles (37%), Cu 3 BiS 3 nanorods (40.7%), and Au/Cu 2- x S nanocrystals (43.2%). They further functionalize with transactivator of transcription (TAT) moiety for cell nuclear-targeting and biodegradable hollow mesoporous MnO 2 (≈100 nm) loaded with photosensitizer Ce6 (TAT-Pd@Au/Ce6/PAH/H-MnO 2 ) to construct a hierarchical targeting nanoplatform. The as-made TAT-Pd@Au/Ce6/PAH/H-MnO 2 demonstrates good premature renal clearance escape ability and increased tumor tissue accumulation. It can be degraded in acidic TME and generate O 2 by reacting to endogenous H 2 to relieve the hypoxia for enhanced PDT, while the released small TAT-Pd@Au nanoplates can effectively enter into the nucleus to mediate PTT. As a result, a remarkable therapeutic effect is achieved owing to the synergistic PTT/PDT therapy. This hierarchical targeting, TME-responsive, cytoplasm hypoxia relief PDT, and nuclear NIR-II PTT synergistic therapy can pave a new avenue for nanomaterials-based cancer therapy.2 to relieve the hypoxia for enhanced PDT, while the released small TAT-Pd@Au nanoplates can effectively enter into the nucleus to mediate PTT. As a result, a remarkable therapeutic effect is achieved owing to the synergistic PTT/PDT therapy. This hierarchical targeting, TME-responsive, cytoplasm hypoxia relief PDT, and nuclear NIR-II PTT synergistic therapy can pave a new avenue for nanomaterials-based cancer therapy., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Sonodynamic therapy (SDT) shows tremendous potential to induce immunogenic cell death (ICD) and activate antitumor immunity. However, it can aggravate hypoxia and release platelet (PLT)-associated danger-associated molecular patterns (DAMPs), which impede therapeutic efficacy and promote tumor metastasis. In order to solve these problems, a biomimetic decoy (designated as Lipo-Ce6/TPZ@M H ) is constructed to reverse the drawbacks of SDT by loading sonosensitizer chlorin e6 (Ce6) and hypoxia-activated tirapazamine (TPZ) in the red blood cells-PLTs hybrid membrane (M H )-camouflaged pH-sensitive liposome. After administration, the decoy exhibits enhanced cancer accumulation and retention abilities due to the immune escape and specific targeting behaviors by biomimetic surface coating. Upon local ultrasound, Ce6 produces toxic reactive oxygen species for SDT, and the resulting hypoxia microenvironment activates TPZ, which can realize a high-effective synergistic therapy. Meanwhile, DAMPs-mediated tumor metastasis is significantly inhibited, because the decoy retains platelet binding functions but is incapable of platelet-mediated metastasis. In addition, ICD-mediated strong antitumor immunities further prevent the growth and metastasis of the residual tumors left behind after synergistic treatment. Taken together, this study highlights the potential of using this cascade therapeutic therapy plus biomemitic decoy in one nanosystem to both eliminate melanoma in situ and suppress lung metastasis., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Recent studies indicate that the synergistic phototherapy (SPT) process can simultaneously generate heat for photothermal therapy (PTT) and singlet oxygen ( 1 O 2 ) for photodynamic therapy (PDT) to overcome the recurrence of tumors. However, the hypoxic environment in tumors seriously limits the therapeutic effect of the oxygen-dependent PDT, leading to the domination of PTT in the SPT process. Therefore, it is urgent to develop a novel SPT platform for overcoming hypoxia in tumors and improving the therapeutic effect of both PTT and PDT. In this work, a novel phototherapeutic platform based on a nanocomposite of aza-BODIPY/manganese dioxide (MnO 2 ) is developed via simple electrostatic self-assembly. In this design, MnO 2 nanosheets, which could produce heat and catalyze endogenous hydrogen peroxide (H 2 O 2 ) to generate oxygen, are prepared as a nanocarrier. After being coated with the as-prepared water-soluble aza-BODIPY-based polymer (PPAIB), the obtained MnO 2 @PPAIB performs as a smart phototherapeutic agent for enhancing the efficiency of both PTT and PDT. More importantly, compared to PPAIB, MnO 2 @PPAIB generates more heat and reactive oxygen species to realize the enhanced therapy effects of PTT and PDT. Hence, this work provides a new method to enhance the therapeutic efficacy of SPT by using a polymer/MnO 2 nanoplatform to improve the oxygen concentration and produce more heat., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Two-dimensional (2D) MXenes, as a new 2D functional material nanosystem, have been extensively explored for broad applications. However, their specific performance and applications in theranostic nanomedicine have still rarely been explored. This work reports on the drug-delivery performance and synergistic therapeutic efficiency of Ti 3 C 2 MXenes for highly efficient tumor eradication. These Ti 3 C 2 MXenes not only possess high drug-loading capability of as high as 211.8%, but also exhibit both pH-responsive and near infrared laser-triggered on-demand drug release. Especially, based on the high photothermal-conversion capability of Ti 3 C 2 MXenes, they have been further explored for efficient tumor eradication by synergistic photothermal ablation and chemotherapy, which has been systematically demonstrated both in vitro and in vivo. These Ti 3 C 2 MXenes have also been demonstrated as the desirable contrast agents for photoacoustic imaging, showing the potential for diagnostic-imaging guidance and monitoring during therapy. The high in vivo histocompatibility of Ti 3 C 2 and their easy excretion out of the body have been evaluated and demonstrated, showing the potential high biosafety for further clinical translation. This work paves a new way for broadening biomedical applications of MXenes in nanomedicine where they can exert the high performance and functionality for synergistic therapy, especially on combating cancer., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A dual-layer shell hollow nanostructure as drug carrier that provides instant on/off function for drug release and contrast enhancement for multimodal imaging is reported. The on-demand drug release is triggered by irradiation of an external magnetic field. The nanocarrier also demonstrates a high drug loading capacity and synergistic magnetic-thermal and chemotherapy., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The combination of photothermal therapy (PTT) with gene therapy (GT) to improve PTT efficiency and thus eliminate cancer cells under mild hyperthermia is highly needed. Herein, multifunctional WS 2 @poly(ethylene imine) (WS 2 @PEI) nanoplatform has been designed and constructed for gene-photothermal synergistic therapy of tumors at mild condition. After a surface modification of WS 2 with a positively charged PEI, the as-prepared WS 2 @PEI nanoplatform can not only act as an efficient survivin-siRNA carrier for GT but also exhibit remarkable near-infrared (NIR) photothermal effects for PTT. On the one hand, the photothermal effects induced by WS 2 @PEI upon NIR irradiation can enhance the cellular uptake owing to the increase of the cell membrane permeability, which leads to the remarkable enhancement of silencing efficiency of survivin. On the other hand, the silencing of survivin can increase the apoptosis as well as reduce the heat resistance of cancer cells by downregulating the heat shock protein 70 expressions, which greatly enhance the sensitivity of cancer cells to PTT. As a result, compared to PTT or GT treatment alone, WS 2 @PEI mediated synergistic GT/PTT therapy remarkably enhances in vitro cancer cell damage and in vivo tumor elimination., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)