Bimetallic Nanomaterials: A Promising Nanoplatform for Multimodal Cancer Therapy

Bimetallic nanomaterials (BMNs) composed of two different metal elements have certain mixing patterns and geometric structures, and they often have superior properties than monometallic nanomaterials. Bimetallic-based nanomaterials have been widely investigated and extensively used in many biomedical fields especially cancer therapy because of their unique morphology and structure, special physicochemical properties, excellent biocompatibility, and synergistic effect. However, most reviews focused on the application of BMNs in cancer diagnoses (sensing, and imaging) and rarely mentioned the application of the treatment of cancer. The purpose of this review is to provide a comprehensive perspective on the recent progress of BNMs as therapeutic agents. We first introduce and discuss the synthesis methods, intrinsic properties (size, morphology, and structure), and optical and catalytic properties relevant to cancer therapy. Then, we highlight the application of BMNs in cancer therapy (e.g., drug/gene delivery, radiotherapy, photothermal therapy, photodynamic therapy, enzyme-mediated tumor therapy, and multifunctional synergistic therapy). Finally, we put forward insights for the forthcoming in order to make more comprehensive use of BMNs and improve the medical system of cancer treatment.     

Liquid Metal as Bioinspired and Unusual Modulator in Bioorthogonal Catalysis for Tumor Inhibition Therapy

Bioorthogonal catalysis mediated by Pd-based transition metal catalysts has sparked increasing interest in combating diseases. However, the catalytic and therapeutic efficiency of current Pd⁰ catalysts is unsatisfactory. Herein, inspired by the concept that ligands around metal sites could enable enzymes to catalyze astonishing reactions by changing their electronic environment, a LM-Pd catalyst with liquid metal (LM) as an unusual modulator has been designed to realize efficient bioorthogonal catalysis for tumor inhibition. The LM matrix can serve as a “ligand” to afford an electron-rich environment to stabilize the active Pd⁰ and promote nucleophilic turnover of the π-allylpalladium species to accelerate the uncaging process. Besides, the photothermal properties of LM can lead to the enhanced removal of tumor cells by photo-enhanced catalysis and photothermal effect. We believe that our work will broaden the application of LM and motivate the design of bioinspired bioorthogonal catalysts.     

A DNA-Gated and Self-Protected Bioorthogonal Catalyst for Nanozyme-Assisted Safe Cancer Therapy

Transition metal catalysts (TMCs) mediated bioorthogonal uncaging catalysis has sparked increasing interest in prodrug activation. However, due to their “always-on” catalytic activity as well as the complex and catalytic-detrimental intracellular environment, the biosafety and therapeutic efficiency of TMCs are unsatisfactory. Herein, a DNA-gated and self-protected bioorthogonal catalyst has been designed by modifying nanozyme-Pd⁰ with highly programmable nucleic acid (DNA) molecules to achieve efficient intracellular drug synthesis for cancer therapy. Monolayer DNA molecules could endow the catalyst with targeting and perform as a gatekeeper to achieve selective prodrug activation within cancer cells. Meanwhile, the prepared graphitic nitrogen-doped carbon nanozyme with glutathione peroxidase (GPx) and catalase (CAT)-like activities could improve the catalytic-detrimental intracellular environment to prevent the catalyst from being inactivated and sensitize the subsequent chemotherapy. Overall, we believe that our work will promote the development of secure and efficient bioorthogonal catalytic systems and provide new insights into novel antineoplastic platforms.     

Biocompatible Polymer-Modified Nanoplatform for Ferroptosis-Enhanced Combination Cancer Therapy

Ferroptosis is a novel type of iron-dependent non-apoptotic pathway that regulates cell death and shows unique mechanisms including causing lipid peroxide accumulation, sensitizing drug-resistant cancers, priming immunity by immunogenic cell death, and cooperatively acting with other anticancer modalities for eradicating aggressive malignancies and tumor relapse. Recently, there has been a great deal of effort to design and develop anticancer biocompatible polymeric nanoplatforms including polypeptide and PEGylated ones to achieve effective ferroptosis therapy (FT) and synergistic combination therapies including chemotherapy (CT), photodynamic therapy (PDT), sonodynamic therapy (SDT), photothermal therapy (PTT), gas therapy (GT) including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S), and immunotherapy (IT). To be noted, the combo therapies such as FT-CT, FT-PTT, FT-GT, and FT-IT are attracting much efforts to fight against intractable and metastatic tumors as they can generate synergistic antitumor effects and immunogenic cell death (ICD) effects or modulate immunosuppressive tumor microenvironments to initiate strong antitumor immunity and memory effects. The polymeric Fenton nano-agents with good biosafety and high anticancer efficacy will provide a guarantee for their applications. In this review, various biocompatible polymer-modified nanoplatforms designed for FT and combo treatments are summarized for anticancer therapies and discussed for potential clinical transitions.     

A Polyoxometalate-Based Pathologically Activated Assay for Efficient Bioorthogonal Catalytic Selective Therapy

Since polyoxometalates (POMs) can undergo reversible multi-electron redox transformations, they have been used to modulate the electronic environment of metal nanoparticles for catalysis. Besides, POMs possess unique electronic structures and acid-responsive self-assembly ability. These properties inspired us to tackle the drawbacks of the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction in biomedical applications, such as low catalytic efficiency and unsatisfactory disease selectivity. Herein, we construct molybdenum (Mo)-based POM nanoclusters doped with Cu (Cu-POM NCs) as a highly efficient bioorthogonal catalyst, which is responsive to pathologicallyacid and H₂S for selective antibiofilm therapy. Leveraging the merits of POMs, the Cu-POM NCs exhibit biofilm-responsive self-assembly behavior, efficient CuAAC-mediated in situ synthesis of antibacterial molecules, and a NIR-II photothermal effect selectively triggered by H₂S in pathogens. The consumption of bacterial H₂S at the pathological site by Cu-POM NCs extremely decreases the number of persisterbacteria, which is conducive to the inhibition of bacterial tolerance and elimination of biofilms. Unlocked at pathological sites and endowed with NIR-II photothermal property, the constructed POM-based bioorthogonal catalytic platform provides new insights into the design of efficient and selective bioorthogonal catalysts for disease therapy.     

Bioorthogonal Turn-On BODIPY-Peptide Photosensitizers for Tailored Photodynamic Therapy

Photodynamic therapy (PDT) leads to cancer remission via the production of cytotoxic species under photosensitizer (PS) irradiation. However, concomitant damage and dark toxicity can both hinder its use. With this in mind, we have implemented a versatile peptide-based platform of bioorthogonally activatable BODIPY-tetrazine PSs. Confocal microscopy and phototoxicity studies demonstrated that the incorporation of the PS, as a bifunctional module, into a peptide enabled spatial and conditional control of singlet oxygen (¹O₂) generation. Comparing subcellular distribution, PS confined in the cytoplasmic membrane achieved the highest toxicities (IC₅₀=0.096±0.003 μm ) after activation and without apparent dark toxicity. Our tunable approach will inspire novel probes towards smart PDT.     

A Sweet Polydopamine Nanoplatform for Synergistic Combination of Targeted Chemo‐Photothermal Therapy

Inspired by sweet or sugar‐coated bullets that are used for medications in clinics and the structure and function of biological melanin, a novel kind of sweet polydopamine nanoparticles and their anticancer drug doxorubicin loaded counterparts are prepared, which integrate an active targeting function, photothermal therapy, and chemotherapy into one polymeric nanocarrier. The oxidative polymerization of lactosylated dopamine and/or with dopamine are performed under mild conditions and the resulting sweet nanoparticles are thoroughly characterized. When exposed to an 808 nm continuous‐wave diode laser, the magnitude of temperature elevation not only increases with the concentration of nanoparticles, but can also be tuned by the laser power density. The nanoparticles possess strong near infrared light absorption, high photothermal conversion efficiency, and good photostability. The nanoparticles present tunable binding with RCA₁₂₀ lectin and a targeting effect to HepG2 cells, confirmed by dynamic light scattering, turbidity analysis, MTT assay, and flow cytometry. Importantly, the sweet nanoparticles give the lowest IC₅₀ value of 11.67 μg mL⁻¹ for chemo‐photothermal therapy compared with 43.19 μg mL⁻¹ for single chemotherapy and 67.38 μg mL⁻¹ for photothermal therapy alone, demonstrating a good synergistic effect for the combination therapy.     

Exploring the Biocompatibility of Zwitterionic Copolymers for Controlling Macrophage Phagocytosis of Bacteria

This paper provides a biomaterial derived from zwitterionic polymer for controlling macrophage phagocytosis of bacteria. A series of zwitterionic copolymers, named DMAPS‐co‐AA, are synthesized with 3‐dimethyl (methacryloyloxyethyl) ammonium propane sulfonate (DMAPS) and acrylic acid (AA). The biocompatibility of DMAPS‐co‐AA copolymers can be adjusted by adjusting the DMAPS‐content or pH value. As the DMAPS‐content increases, the biocompatibility of zwitterionic copolymer increases. The zwitterionic copolymers with DMAPS content above 30 wt% have higher biocompatibility. Moreover, the biocompatibility also increases significantly as the pH increases from 3.4 to 7.2. By adjusting the pH above 5.8, the zwitterionic copolymer with lower DMAPS‐content also shows higher biocompatibility. Importantly, after incubation with the DMAPS‐co‐AA copolymer solutions at different pH values, phagocytosis behavior of macrophage RAW264.7 cells can also be adjusted. The phagocytosis of bacteria is enhanced at pH = 7.2. Thus, it is proposed that zwitterionic copolymers can be used for controlling phagocytosis of bacteria.

     

A General Strategy for Macrotheranostic Prodrug Activation: Synergy between the Acidic Tumor Microenvironment and Bioorthogonal Chemistry

Prodrugs activated by endogenous stimuli face the problem of tumor heterogeneity. Bioorthogonal prodrug activation that utilizes an exogenous click reaction has the potential to solve this problem, but most of the strategies currently used rely on the presence of endogenous receptors or overexpressed enzymes. We herein integrate the acidic, extracellular microenvironment of a tumor and a click reaction as a general strategy for prodrug activation. This was achieved by using a tumor pH‐responsive polymer containing tetrazine groups, which formed unreactive micelles in the blood but disassembled in response to tumor pH. The vinyl ether group on the macrotheranostic prodrug (CyPVE) is activated by the tetrazine groups, which was confirmed by tumor‐specific fluorescence activation and phototoxicity restoration. Therefore, the bioorthogonal reactions in the context of the ubiquitous acidic tumor microenvironment can provide a general strategy for bioorthogonal prodrug activation.     

肿瘤靶向Pt-Cu基纳米平台用于近红外二区光声成像引导的光热治疗

基于层层（LBL）自组装技术,在Pt-Cu纳米合金表面依次包覆带正电的聚赖氨酸（PLL）和带负电的透明质酸（HA）,成功构筑Pt-Cu@PLL@HA纳米平台。HA不仅延长了纳米平台血液循环时间,还可实现肿瘤主动靶向作用,提升肿瘤部位富集效果。在肿瘤区域透明质酸酶（HAase）作用下HA快速降解,释放Pt-Cu@PLL （+）颗粒,有利于肿瘤细胞特异性摄取。基于Pt-Cu合金良好的近红外二区（NIR-Ⅱ）吸收性能,实现了NIR-Ⅱ光声成像引导的NIR-Ⅱ光热高效抗肿瘤效果。     

用于肿瘤综合治疗的无机纳米材料

无机纳米材料以其独特的纳米特性,在以肿瘤为代表的多种疾病的诊疗一体及综合治疗中具有越来越广泛的应用。本文重点关注该领域代表性的三类材料：超顺磁性氧化铁纳米粒、上转换纳米粒以及贵金属纳米粒,它们分别具有优异的磁学性能、光学性能及热性能,归纳总结了它们在体外检测、活体成像、药物输送以及靶向治疗等方面的应用及其优势与劣势,希望为发展生物相容性更好、诊疗效果更佳的无机纳米材料提供更好参考和建议,促进无机纳米材料的临床转化。     

Bioorthogonal SERS Nanoprobes for Mulitplex Spectroscopic Detection,Tumor Cell Targeting,and Tissue Imaging

A surface‐enhanced Raman scattering (SERS) technique shows extraordinary features for a range of biological and biomedical applications. Herein, a series of novel bioorthogonal SERS nanoprobes were constructed with Gold nanoflower (AuNF) and Raman reporters, the signals of which were located in a Raman‐silent region of biological samples. AS1411 aptamer was also co‐conjugated with AuNF through a self‐assembled monolayer coverage strategy. Multiplex SERS imaging using these nanoprobes with three different bioorthogonal small‐molecule Raman reporters is successfully achieved with high multiplexing capacity in a biologically Raman‐silent region. These Raman nanoprobes co‐conjugated with AS1411 showed high affinity for tumor cells with overexpressed nucleolin and can be used for selective tumor cell screening and tissue imaging.     

A Ferroptosis-Inducing Arsenene-Iridium Nanoplatform for Synergistic Immunotherapy in Pancreatic Cancer

Due to multidrug resistance and the high risk of recurrence, effective and less toxic alternative pancreatic cancer treatments are urgently needed. Pancreatic cancer cells are highly resistant to apoptosis but sensitive to ferroptosis. In this study, an innovative nanoplatform ( AsIr@PDA ) was developed by electrostatic adsorption of a cationic iridium complex ( IrFN ) onto two-dimensional (2D) arsenene nanosheets. This nanoplatform exhibits superior ferroptosis-inducing effects with high drug loading capacity and, importantly, excellent anti-cancer immune activation function, leading to efficient elimination of pancreatic tumors with no observable side effects. Interestingly, AsIr@PDA significantly prevents the recurrence of pancreatic cancer in vivo when compared with a cisplatin-loaded nanoplatform. This designed nanoplatform demonstrated superior therapeutic efficacy by synergistic ferroptosis-induced chemotherapy with immunotherapy via an all-in-one strategy, providing new insights for future pancreatic cancer therapy.     

纳米材料在肿瘤光动力治疗中的研究进展

光动力治疗是新兴的非侵入性癌症治疗方法。纳米材料以其独特的结构以及光物理、光化学性质成为可用于光动力治疗的光敏剂。根据纳米材料的不同种类,分别对无机非金属纳米材料、无机金属纳米材料、有机小分子纳米材料以及有机聚合物纳米材料等的构建策略及其在光动力治疗肿瘤中的应用进行综述。展望了纳米材料在未来肿瘤光动力治疗中的挑战和发展方向。为新一代纳米光敏剂的构建提供创新思路,并扩展其在癌症治疗中的潜力。     

A Genetically Encoded Isonitrile Lysine for Orthogonal Bioorthogonal Labeling Schemes

Bioorthogonal click-reactions represent ideal means for labeling biomolecules selectively and specifically with suitable small synthetic dyes. Genetic code expansion (GCE) technology enables efficient site-selective installation of bioorthogonal handles onto proteins of interest (POIs). Incorporation of bioorthogonalized non-canonical amino acids is a minimally perturbing means of enabling the study of proteins in their native environment. The growing demand for the multiple modification of POIs has triggered the quest for developing orthogonal bioorthogonal reactions that allow simultaneous modification of biomolecules. The recently reported bioorthogonal [4 + 1] cycloaddition reaction of bulky tetrazines and sterically demanding isonitriles has prompted us to develop a non-canonical amino acid (ncAA) bearing a suitable isonitrile function. Herein we disclose the synthesis and genetic incorporation of this ncAA together with studies aiming at assessing the mutual orthogonality between its reaction with bulky tetrazines and the inverse electron demand Diels–Alder (IEDDA) reaction of bicyclononyne (BCN) and tetrazine. Results showed that the new ncAA, bulky-isonitrile-carbamate-lysine (BICK) is efficiently and specifically incorporated into proteins by genetic code expansion, and despite the slow [4 + 1] cycloaddition, enables the labeling of outer membrane receptors such as insulin receptor (IR) with a membrane-impermeable dye. Furthermore, double labeling of protein structures in live and fixed mammalian cells was achieved using the mutually orthogonal bioorthogonal IEDDA and [4 + 1] cycloaddition reaction pair, by introducing BICK through GCE and BCN through a HaloTag technique.     

A Light-Responsive Injectable Hydrogel with Remodeling Tumor Microenvironment for Light-Activated Chemodynamic Therapy

Chemodynamic therapy (CDT) based on Fenton-like reaction is often limited by the tumor microenvironment (TME), which has insufficient hydrogen peroxide, and single CDT treatment is often less efficacious. To overcome these limitations, a hydrogel-based system is designed to enhance the redox stress (EOH) by loading the composite nanomaterial Cu-Hemin-Au, into the agarose hydrogels. The hydrogels can reach the tumor site upon intratumoral injection, and then coagulate and stay for extended period. Once irradiated with near-infrared light, the Cu-Hemin-Au act as a photothermal agent to convert the light energy into heat, and the EOH gradually heated up and softened, releasing the Cu-Hemin-Au residing in it to achieve photothermal therapy (PTT). Benefiting from the glucose oxidase (GOx)-like activity of the Au nanoparticles, glucose in the tumor cells is largely consumed, and hydrogen peroxide (H₂O₂) is generated in situ, and then Cu-Hemin-Au react with sufficient H₂O₂ to generate a large amount of reactive oxygen species, which promote the complete inhibition of tumor growth in mice during the treatment cycle. The hydrogel system for the synergistic enhancement of oxidative stress achieves good PTT/CDT synergy, providing a novel inspiration for the next generation of hydrogels for application in antitumor therapy.     

A Remotely Controlled Nanosystem for Spatiotemporally Specific Gene Regulation and Combinational Tumor Therapy

The dearth of technologies that allow gene modulation and therapy with high spatiotemporal precision remains a bottleneck in biomedical research and applications. Here we present a near-infrared (NIR) light-controlled nanosystem that allows spatiotemporally controlled regulation of gene expression and thus combinational tumor therapy. The nanosystem is built by engineering of an enzyme-activatable antisense oligonucleotide and further combination with an upconversion nanoparticle-based photodynamic system and a mitochondria localization signal. The system relies on photodynamic effect-induced translocation of a DNA repair enzyme from nucleus into mitochondria, which enables spatially selective gene regulation via enzymatic reactions. We demonstrate that the NIR light-induced mitochondrial photodamage and gene regulation enable enhanced antitumor effect. Our approach may enable the specific gene regulation and tumor treatment with high precision both spatially and temporally.     

Innovative Strategies for Hypoxic‐Tumor Photodynamic Therapy

Despite its clinical promise, photodynamic therapy (PDT) suffers from a key drawback associated with its oxygen‐dependent nature, which limits its effective use against hypoxic tumors. Moreover, both PDT‐mediated oxygen consumption and microvascular damage further increase tumor hypoxia and, thus, impede therapeutic outcomes. In recent years, numerous investigations have focused on strategies for overcoming this drawback of PDT. These efforts, which are summarized in this review, have produced many innovative methods to avoid the limits of PDT associated with hypoxia.     

功能化金属-有机框架材料在肿瘤治疗中的研究进展

恶性肿瘤由于其易转移、复发等特点,已经严重危害到人类的生命健康.近年来,研究人员设计了大量纳米药物载体,将抗肿瘤药物安全有效地运载到肿瘤,有效地提高了药效并降低了毒副作用.金属有机框架材料（metal-organic frameworks,MOFs）是一类有序、多孔的晶态材料,具有比表面积大、结构可设计性强、易生物降解等独特优势,已经被广泛应用于气体吸附与分离、催化、药物传递、生物大分子固载以及肿瘤治疗等方面.目前,基于MOFs的生物医用研究主要集中在MOF材料的可控合成,表面修饰,基于MOF独特理化性质发展的多模式成像技术以及肿瘤靶向的药物运载技术等几个方面.主要介绍了基于MOFs构建的生物功能化材料在肿瘤治疗中的应用,并对其在生物医学领域的应用进行了展望.     

Tumor Microenvironment Responsive Single-Atom Nanozymes for Enhanced Antitumor Therapy

Single-atom nanozymes (SAzymes) with specific response to the unique tumor microenvironment (TME) feature providing 100 % metal atoms utilization for high-efficient enzyme-catalyzed therapy and accurate template for the study of therapeutic mechanisms. In this review, we first introduce the various synthetic strategies of SAzymes, and the TME-responsive SAzymes activities. Next, the TME-responsive enhanced antitumor therapeutic approaches based on the enzymatic activities of SAzymes are summarized, and the corresponding therapy mechanisms are elaborated. Subsequently, a concise but concentrated summary, and the challenges and opportunities for the future design and engineering of SAzyme are outlined. As a new discipline, SAzymes have vast space for development in enhanced antitumor therapy. This timely review provides guidance and constructive suggestions for the future of SAzymes.