Multimode Therapy Research Articles

Design of multifunctional theranostic nanoplatforms with glutathione-triggered H2S generation and H2S-activitated multi-modal therapy

Hydrogen sulfide (H2S) is a specific substance in the tumor microenvironment, and highly expressed H2S can be used to activate some agents for intelligent treatment of tumors. However, not all tumors contain overexpressed hydrogen sulfide. To address this obstacle, we report the design of theranostic nanoplatforms with glutathione-triggered H2S generation and H2S-triggered therapy activation functions, by using hollow mesoporous organosilica nanoparticles (HMON) to load Cu-HMME framework nanodots (CuHF) and garlic extract diallyl trisulfide (DATS). Such CuHF/DATS@HMON with sizes of about 110 nm exhibit obvious quenching fluorescence and is inactive. Importantly, when CuHF/DATS@HMON is mixed with glutathione (GSH) solution, the nucleophilic attack of GSH on trisulfide bonds (−S-S-S-) in DATS generates S-allyl glutathione disulfide (GSSA) and allyl perthiol (ASSH), with the latter releasing H2S upon reduction by GSH, conferring the overexpress of H2S as the first-cascade activation. Furthermore, endogenous H2S can react with CuHF to produce CuS nanoparticles with strong chemodynamic/photothermal effect and to release metal porphyrin ((Cu)HMME) with photodynamic effect, as the second-cascade activation. When CuHF/DATS@HMON is accumulated at the tumor site through EPR effect, DATS in the CuHF/DATS@HMON can react with endogenous glutathione (GSH) in cancer cells to in situ generate H2S, and then H2S can vulcanize CuHF to generate CuS nanoparticles and (Cu)HMME complexes, thus realizing chemokinetic, photodynamic and photothermal multi-mode therapy to inhibit tumor growth. At the same time, the tetrasulfide bonds (−S-S-S-S-) in HMON allow the material to be slowly broken down and metabolized. Therefore, this study not only provides a general design for constructing tumor-microenvironment-responsive agents, but also provides some insights for multi-modal therapy of cancers.

Aggregation-Induced Emission Photosensitizer with Ag(I)-π Interaction-Enhanced Reactive Oxygen Species for Eliminating Multidrug Resistant Bacteria.

Multidrug-resistant (MDR) bacteria pose serious threats to public health due to the lack of effective and biocompatible drugs to kill MDR bacteria. Photodynamic antibacterial therapy has been widely studied due to its low induction of resistance. However, photosensitizers that can efficiently generate reactive oxygen species (ROS) through both type I and type II mechanisms and that have the capability of multiple modes of action are rarely reported. Addressing this issue, we developed a near-infrared-emitting triphenylamine indole iodoethane (TTII) and its silver(I) self-assembled (TTIIS) aggregation-induced emission (AIE) photosensitizer for multimode bacterial infection therapy. TTII can efficiently produce both Type I ROS •OH and Type II ROS 1O2. Interestingly, the Ag(I)-π interaction contributed in TTIIS efficiency promotion of the generation of 1O2. Moreover, by releasing Ag+, TTIIS enabled photodynamic-Ag(I) dual-mode sterilization. As a result, TTIIS achieved an effective enhancement of antibacterial activity, with a 1-2-fold boost against multidrug-resistant Escherichia coli (MDR E. coli). Both TTII and TTIIS at a concentration as low as 0.55 μg mL-1 can kill more than 98% of methicillin resistant Staphylococcus aureus (MRSA) on MRSA-infected full-thickness defect wounds of a mouse, and both TTII and TTIIS were effective in eliminating the bacteria and promoting wound healing.

Combining multi-mode thermal therapy with IL-6 and IL-17A neutralization amplifies antitumor immunity to facilitate long-term survival in LLC1-bearing mice

Non-small cell lung cancer (NSCLC) is known for rapid development and chronic inflammation-induced immunosuppression. IL-6 and IL-17A are the essential cytokines that facilitate NSCLC progression and myeloid-derived suppressive cell (MDSC)-mediated evasion. IL-6 or IL-17A targeting, especially IL-6, shown outstanding efficacy in patient NSCLC controlling, but failed to completely eradicate tumor. The local tumor multi-mode thermal therapy developed in our prior research was demonstrated to stimulate systemic and durable tumor-specific immune response thereby promoting long-term tumor-free survival of mice and prolong the progression-free survival of patients, although the therapeutic efficacy was still affected by high-level preoperative MDSCs. To further improve the efficacy, in this study, IL-6 and IL-17A neutralization were combined with multi-mode thermal therapy in mouse LLC1 NSCLC model. Study revealed that combined with single cytokine neutralization only prolonged the survival time while triple combination therapy efficiently improved the survival rate. Additionally, triple combination therapy reduced the accumulation of MDSCs but promoted their maturation with strengthened activation and function of myeloid cells, thereby triggering a Th1-dominant-CD4+ T cell-response and enhancing the malignant cell-killing capacity of immune cells. Our study highlights the extraordinary efficacy of combining multi-mode thermal therapy with IL-6 and IL-17A neutralization, revealing a new strategy for refractory NSCLC patients.Graphical

A MgAl-LDH-CuS nanosheet-based thermo-responsive composite hydrogel with nir-responsive angiogenesis inhibitor releasing capability for multimode starvation therapy

The rapid proliferation of tumors is highly dependent on the nutrition supply of blood vessels. Cutting off the nutrient supply to tumors is an effective strategy for cancer treatment, known as starvation therapy. Although various hydrogel-based biomaterials have been developed for starvation therapy through glucose consumption or intravascular embolization, the limitations of single-mode starvation therapy hinder their therapeutic effects. Herein, we propose a dual-function nutrition deprivation strategy that can block the nutrients delivery through extravascular gelation shrinkage and inhibit neovascularization through angiogenesis inhibitors based on a novel NIR-responsive nanocomposite hydrogel. CuS nanodots-modified MgAl-LDH nanosheets loaded with angiogenesis inhibitor (sorafenib, SOR) are incorporated into the poly(n-isopropylacrylamide) (PNIPAAm) hydrogel by radical polymerization to obtain the composite hydrogel (SOR@LDH-CuS/P). The SOR@LDH-CuS/P hydrogel can deliver hydrophobic SOR with a NIR-responsive release behavior, which could decrease the tumor vascular density and accelerate cancer cells apoptosis. Moreover, the SOR@LDH-CuS/P hydrogel exhibits higher (3.5 times) compressive strength than that of the PNIPAAm, which could squeeze blood vessels through extravascular gelation shrinkage. In vitro and in vivo assays demonstrate that the interruption of nutrient supply by gelation shrinkage and the prevention of angiogenesis by SOR is a promising strategy to inhibit tumor growth for multimode starvation therapy.

The clinical application and novel multi-mode thermal therapy technology

The clinical application and novel multi-mode thermal therapy technology

Bridging host-guest chemistry with molecule chemistry-covalent organic polyrotaxanes (COPRs): from synthesis to inactivation of bacterial pathogens.

As a thriving artificial material, covalent organic frameworks (COFs), boasting inherent structural designability and functional adaptability, and with compositions akin to biological macromolecules, have emerged as a rising star in the field of material science. However, the progression of COFs is significantly impeded by the arduous and intricate preparation procedures of novel building blocks, as well as the inefficient development process of new reactions. An efficient, uncomplicated, and versatile functionalization approach, which has the potential to not only facilitate customized preparation of COFs based on application demands but also enable precise performance control, has become a focal point of research. The formulation of multi-functional COFs through efficient and cost-effective methods poses a critical challenge for the practical application of COFs. This review aims to present the preparation of COFs by amalgamating rigid molecular chemistry with flexible supramolecular host-guest chemistry, adopting a "couple hardness with softness" strategy to meticulously construct intelligent covalent organic polyrotaxanes (COPRs) using conventional reactions. Herein, novel building blocks can be acquired by amalgamating existing macrocycle complexes with framework blocks. The amalgamation of supramolecular chemistry bolsters the capabilities to generate, sense, respond, and amplify distinctive signals, thereby expediting the advancement of multifaceted materials with sophisticated structures. Concurrently, the infusion of supramolecular force endows COPRs with exceptional performance, facilitating multi-mode collaborative antibacterial therapy. This comprehensive review not only promotes the efficient utilization of resources but also stimulates the rapid advancement of framework materials.

Exceedingly Small Magnetic Iron Oxide Nanoparticles for T1 -Weighted Magnetic Resonance Imaging and Imaging-Guided Therapy of Tumors.

Magnetic iron oxide nanoparticles (MIONs) based T2 -weighted magnetic resonance imaging (MRI) contrast agents (CAs) are liver-specific with good biocompatibility, but have been withdrawn from the market and replaced with Eovist (Gd-EOB-DTPA) due to their inherent limitations (e.g., susceptibility to artifacts, high magnetic moment, dark signals, long processing time of T2 imaging, and long waiting time for patients after administration). Without the disadvantages of Gd-chelates and MIONs, the recently emerging exceedingly small MIONs (ES-MIONs) (<5nm) are promising T1 CAs for MRI. However, there are rare review articles focusing on ES-MIONs for T1 -weighted MRI. Herein, the recent progress of ES-MIONs, including synthesis methods (the current basic synthesis methods and improved methods), surface modifications (artificial polymers, natural polymers, zwitterions, and functional protein), T1 -MRI visual strategies (structural remodeling, reversible self-assemblies, metal ions doped, T1 /T2 dual imaging modes, and PET/MRI strategy), and imaging-guided cancer therapy (chemotherapy, gene therapy, ferroptosis therapy, photothermal therapy, photodymatic therapy, radiotherapy, immuotherapy, sonodynamic therapy, and multimode therapy), is summarized. The detailed description of synthesis methods and applications of ES-MIONs in this review is anticipated to attract extensive interest from researchers in different fields and promote their participation in the establishment of ES-MIONs based nanoplatforms for tumor theranostics.

One pot preparation of muti-mode nanoplatform to combat ovarian cancer

Ovarian cancer is one of the most common gynecological cancers with high mortality rate. The battle against ovarian cancer usually impaired by the evolved multidrug resistance (MDR) phenotype as well as metastasis in cancers, which urgently call for the development of multi-mode strategies to overcome the MDR and reduce metastasis. Considering the good benefits of ferroptosis and photothermal therapy (PTT) in cancer management, we herein proposed a facile way to construct nanoparticle platform (Fe-Dox/PVP) composed of ferric chloride, doxorubicin (Dox) and polyvinyl pyrrolidone (PVP) for the multi-mode therapy of ovarian cancer using chemotherapy, ferroptosis and mild hypothermia PTT. Our results demonstrated that Fe-Dox/PVP with mild hypothermia was shown to have improved endosomal escape/drug delivery, enhanced ferroptosis induction and good tumor targeting effects. Most importantly, the integration of all three effects into one platform provided increased anti-metastasis effect and promising in vitro/in vivo anticancer performance with high biocompatibility. In this study, we offer a facile and robust way to prepare a multi-mode nanoplatform to combat ovarian cancer, which can be further extended for the management of many other cancers.

Exploration of the impact of multimode thermal therapy versus radiofrequency ablation on CD8+ T effector cells of liver malignancies based on single cell transcriptomics.

Multimode thermal therapy (MTT) is an innovative interventional therapy developed for the treatment of liver malignancies. When compared to the conventional radiofrequency ablation (RFA), MTT typically offers improved prognosis for patients. However, the effect of MTT on the peripheral immune environment and the mechanisms underlying the enhanced prognosis have yet to be explored. The aim of this study was to further investigate the mechanisms responsible for the difference in prognosis between the two therapies. In this study, peripheral blood samples were collected from four patients treated with MTT and two patients treated with RFA for liver malignancies at different time points before and after the treatment. Single cell sequencing was performed on the blood samples to compare and analyze the activation pathways of peripheral immune cells following the MTT and RFA treatment. There was no significant effect of either therapy on the composition of immune cells in peripheral blood. However, the differential gene expression and pathway enrichment analysis demonstrated enhanced activation of T cells in the MTT group compared to the RFA group. In particular, there was a remarkable increase in TNF-α signaling via NF-κB, as well as the expression of IFN-α and IFN-γ in the CD8+ effector T (CD8+ Teff) cells subpopulation, when compared to the RFA group. This may be related to the upregulation of PI3KR1 expression after MTT, which promotes the activation of PI3K-AKT-mTOR pathway. This study confirmed that MTT could more effectively activate peripheral CD8+ Teff cells in patients compared with RFA and promote the effector function, thus resulting in a better prognosis. These results provide a theoretical basis for the clinical application of MTT therapy.

Fe-Based Metal Organic Frameworks (Fe-MOFs) for Bio-Related Applications.

Metal-organic frameworks (MOFs) are porous materials composed of metal ions and organic ligands. Due to their large surface area, easy modification, and good biocompatibility, MOFs are often used in bio-related fields. Fe-based metal-organic frameworks (Fe-MOFs), as important types of MOF, are favored by biomedical researchers for their advantages, such as low toxicity, good stability, high drug-loading capacity, and flexible structure. Fe-MOFs are diverse and widely used. Many new Fe-MOFs have appeared in recent years, with new modification methods and innovative design ideas, leading to the transformation of Fe-MOFs from single-mode therapy to multi-mode therapy. In this paper, the therapeutic principles, classification, characteristics, preparation methods, surface modification, and applications of Fe-MOFs in recent years are reviewed to understand the development trends and existing problems in Fe-MOFs, with the view to provide new ideas and directions for future research.

Nanomaterials for the treatment of bacterial infection by photothermal/photodynamic synergism.

In the past few decades, great progress has been made in the field of nanomaterials against bacterial infection. However, with the widespread emergence of drug-resistant bacteria, people try their best to explore and develop new antibacterial strategies to fight bacteria without obtaining or increasing drug resistance. Recently, multi-mode synergistic therapy has been considered as an effective scheme for the treatment of bacterial infections, especially the combination of photothermal therapy (PTT) and photodynamic therapy (PDT) with controllable, non-invasive, small side effects and broad-spectrum antibacterial characteristics. It can not only improve the efficiency of antibiotics, but also do not promote antibiotic resistance. Therefore, multifunctional nanomaterials which combine the advantages of PTT and PDT are more and more used in the treatment of bacterial infections. However, there is still a lack of a comprehensive review of the synergistic effect of PTT and PDT in anti-infection. This review first focuses on the synthesis of synergistic photothermal/photodynamic nanomaterials and discusses the ways and challenges of photothermal/photodynamic synergism, as well as the future research direction of photothermal/photodynamic synergistic antibacterial nanomaterials.

Molecular Engineering of NIR-II/IIb Emitting AIEgen for Multimodal Imaging-Guided Photo-Immunotherapy.

In view of the great challenges related to the complexity and heterogeneity of tumors, efficient combination therapy is an ideal strategy for eliminating primary tumors and inhibiting distant tumors. A novel aggregation-induced emission (AIE) phototherapeutic agent called T-TBBTD is developed, which features a donor-acceptor-donor (D-A-D) structure, enhanced twisted molecule conformation, and prolonged second near-infrared window (NIR-II) emission. The multimodal imaging function of the molecule has significance for its treatment time window and excellent photothermal/photodynamic performance for multimode therapy. The precise molecular structure and versatility provide prospects for molecular therapy for anti-tumor applications. Fluorescence imaging in the NIR-II window offers advantages with enhanced spatial resolution, temporal resolution, and penetration depth. The prepared AIE@R837 NPs also have controllable performance for antitumor photo-immunotherapy. Following local photo-irradiation, AIE@R837 NPs generate abundant heat, and 1 O2 directly kills tumor cells, induces immunogenic cell death (ICD) as a photo-therapeutic effect, and releases R837, which enhances the synergistic effect of antigen presentation and contributes to the long-lasting protective antitumor immunity. A bilateral 4T1 tumor model revealed that this photo-immunotherapy can eliminate primary tumors. More importantly, it has a significant inhibitory effect on distant tumor growth. Therefore, this method can provide a new strategy for tumor therapy.

A multifunctional nanocomposite coated with a BSA membrane for cascaded nitric oxide therapy

Gas therapy based on nitric oxide (NO) has emerged as a potential therapeutic approach for cancer, and in conjunction with multi-mode combination therapy, offers new possibilities for achieving significant hyperadditive effects. In this study, an integrated AI-MPDA@BSA nanocomposite for diagnosis and treatment was constructed for PDA based photoacoustic imaging (PAI) and cascade NO release. Natural NO donor L-arginine (L-Arg) and photosensitizer (PS) IR780 were loaded into mesoporous polydopamine (MPDA). Bovine serum albumin (BSA) was conjugated to the MPDA to increase the dispersibility and biocompatibility of the nanoparticles, as well as to serve as a gatekeeper controlling IR780 release from the MPDA pores. The AI-MPDA@BSA produced singlet oxygen (1O2) and converted it into NO through a chain reaction based on L-Arg, enabling a combination of photodynamic therapy and gas therapy. Moreover, due to the photothermal properties of MPDA, the AI-MPDA@BSA performed good photothermal conversion, which allowed photoacoustic imaging. As expected, both in vitro and in vivo studies have confirmed that the AI-MPDA@BSA nanoplatform has a significant inhibitory effect on cancer cells and tumors, and no apparent systemic toxicity or side effects were detected during the treatment period.

Multifunctional DNA nanoprobe for tumor-targeted synergistic therapy by integrating chemodynamic therapy with gene silencing.

Due to the high complexity, diversity and heterogeneity of tumor occurrence and development, multi-mode synergistic therapy is more effective than single treatment modes to improve the antitumor efficacy. Also, multifunctional probes are crucial to realize synergistic therapy. Herein, a multifunctional DNA tetrahedron nanoprobe was ingeniously designed to simultaneously achieve chemodynamic therapy (CDT) and gene silencing for synergistic antitumor. The multifunctional DNA tetrahedron nanoprobe, DNA tetrahedron-silver nanocluster-antagomir-21 (D-sgc8-DTNS-AgNCs-Anta-21), integrated a CDT reagent (DNA-AgNCs) and miRNA-21 inhibitor (Anta-21) with a specific recognition probe (aptamer). After targeted entry in cancer cells, D-sgc8-DTNS-AgNCs-Anta-21 silenced endogenous miRNA-21 by Anta-21 and produced highly toxic ˙OH by reacting with H2O2, which induced apoptosis in the tumor cells. The targeted recognition of aptamers led to the concentration-dependent death of HeLa cells. On the contrary, the cell survival rate of normal cells was basically unaffected with an increase in the concentration of D-sgc8-DTNS-AgNCs-Anta-21. Therefore, the diverse functions, biocompatibility and programmability of DNA provide a useful and easy way to assemble multifunctional probes for synergistic therapy.

Upconversion Nanoparticles for Cancer Therapy

Cancer Therapies In article number 2200092, Yang Li and Guanying Chen summarize the fundamental roles of Lanthanidedoped upconversion nanoparticles in cancer therapy and highlight types of cell death caused by excess reactive oxygen species and also highlight cutting-edge applications in multimode cancer therapy and imaging-guided cancer therapy.

Facile synthesis of Au NCs@POMA-Fe-FA nanoregulators with precise-targeted/NIR-laser-triggered/tumor microenvironment-responsive abilities for enhanced photothermal /photodynamic/chemodynamic therapy with photothermal imaging guidence

For overcoming the insurmountable obstacles of the multimodal combined therapy (MCT) in anti-cancer, tumor microenvironment regulation is considered an effective method. Hence, a TME adjustable, precise-targeted and near-infrared (NIR)-laser-responsive Au nanoclusters (NCs)@poly-o-mercaptoaniline (POMA)-Fe nanoregulators (NRGs) grafting with folic acid (FA) was designed and successfully fabricated by a simple redox with coordination method. The obtained Au NCs@POMA-Fe-FA NRGs could achieve the excellent TME regulation ability via the following avenues: the Fe3+ ions are released by the acidic TME from the POMA-Fe-FA shell to transform the hydrogen peroxide (H2O2) into O2 for overcoming the hypoxia of TME. Further, the massive Fe3+ ions are reduced by the excessive glutathione (GSH) in TME into Fe2+ ions, which further react with H2O2 to produce the hydroxyl radical (·OH) by Fenton reaction, realizing the chemodynamic therapy (CDT) to tumor. Moreover, the Au NC cores and the POMA-Fe-FA shell endow the nanoregulators with outstanding photodynamic and photothermal abilities triggered by NIR laser respectively. In addition, the consumption of GSH enhances the photodynamic therapy (PDT) and CDT synergistically. More importantly, the FA-induced targeting and NIR guided photothermal imaging grant the obtained nanoregulators outstanding selectivity for the precise tumor treatment and minimized side effect. The in vivo experimental results displayed that the tumor inhibition of the prepared Au NCs@POMA-Fe-FA NRGs could reach as high as about 84%. Obviously, the synthesized Au NCs@POMA-Fe-FA NRGs pave a new path for the design and preparation of novel multi-mode therapy for cancer with regulatory effects to TME.

Lotus Seedpod-Inspired Crosslinking-Assembled Hydrogels Based on Gold Nanoclusters for Synergistic Osteosarcoma Multimode Imaging and Therapy.

Osteosarcoma is difficult to be resected through surgical operations without damage to the bone matrix, while chemotherapy and radiotherapy induce inevitable systemic injury. It is still a major challenge to develop a novel treatment suitable for the complex anatomical structure of the bone. Herein, inspired by lotus seedpods, injectable hydrogels with long-term retention for synergistic osteosarcoma treatment were developed. Gold nanoclusters (GNCs) with strong fluorescence (FL) and computed tomography (CT) imaging effects represented the lotus seeds. The oxidized hyaluronic acid (HA-ALD) chain resembled the stem. HA-ALD and GNCs form crosslinking-assembled hydrogels abbreviated as HG-CAHs through dynamic amide bonds. Compared with DNA-, pH-, and light-mediated assembly, this in situ method induces enhanced photothermal therapy (PTT) ability, ensures high biocompatibility, and retains the imaging function of GNCs, which contribute to lighting up osteosarcoma persistently for further diagnosis and treatment. In addition, the HG-CAHs with outstanding mechanical properties are similar to the lotus seedpods with supportive force and a typical porous structure. They are favorable for the local pH- and near-infrared (NIR)-responsive release of doxorubicin (Dox) owing to the acidic osteosarcoma microenvironment and the Brownian movement. The HG-CAHs ablate osteosarcoma efficiently and reduce metabolic toxicity significantly, which will aid in the development of a new generation of osteosarcoma treatments.

Facile Synthesis of Fe3O4@Au/PPy-DOX Nanoplatform with Enhanced Glutathione Depletion and Controllable Drug Delivery for Enhanced Cancer Therapeutic Efficacy

The complex physiological environment and inherent self-healing function of tumors make it difficult to eliminate malignant tumors by single therapy. In order to enhance the efficacy of antitumor therapy, it is significant and challenging to realize multi-mode combination therapy by utilizing/improving the adverse factors of the tumor microenvironment (TME). In this study, a novel Fe3O4@Au/PPy nanoplatform loaded with a chemotherapy drug (DOX) and responsive to TME, near-infrared (NIR) laser and magnetic field was designed for the combination enhancement of eliminating the tumor. The Fe2+ released at the low pH in TME can react with endogenous H2O2 to induce toxic hydroxyl radicals (·OH) for chemodynamic therapy (CDT). At the same time, the generated Fe3+ could deplete overexpressed glutathione (GSH) at the tumor site to prevent reactive oxygen species (ROS) from being restored while producing Fe2+ for CDT. The designed Fe3O4@Au/PPy nanoplatform had high photothermal (PT) conversion efficiency and photodynamic therapy (PDT) performance under NIR light excitation, which can promote CDT efficiency and produce more toxic ROS. To maximize the cancer-killing efficiency, the nanoplatform can be successfully loaded with the chemotherapeutic drug DOX, which can be efficiently released under NIR excitation and induction of slight acidity at the tumor site. In addition, the nanoplatform also possessed high saturation magnetization (20 emu/g), indicating a potential magnetic targeting function. In vivo and in vitro results identified that the Fe3O4@Au/PPy-DOX nanoplatform had good biocompatibility and magnetic-targeted synergetic CDT/PDT/PTT/chemotherapy antitumor effects, which were much better than those of the corresponding mono/bi/tri-therapies. This work provides a new approach for designing intelligent TME-mediated nanoplatforms for synergistically enhancing tumor therapy.

Volbots: Volvox Microalgae‐Based Robots for Multimode Precision Imaging and Therapy

AbstractBiohybrid microrobotics are exploited as a delivery approach to actively transport therapeutic payload to tumors. However, the therapeutic utility of this approach can be diminished by tumor hypoxia. Moreover, current biohybrid microrobotics design is mainly focused on the living organisms’ motility and biocompatibility, yet the unique biological function of the natural organism is often overlooked. Here, an all‐in‐one self‐propelled volvox‐based multifunctional robot, that is, Volbot, with built‐in capabilities of fluid mixing, multimode imaging, and photosynthesis‐mediated in situ oxygen generation that can potentially relieve hypoxia is developed. Volbots can follow a pre‐specified route and directionality under the control of a magnetic field. Red‐light irradiation (λ = 650 nm) can enhance the Volbot's locomotive behavior, enhance the mixing of biofluids, and modulate the oxygen production to improve the efficacy of photodynamic therapy. Moreover, Volbots can absorb near‐infrared irradiation and produce localized hyperthermia to treat tumors. Subcutaneous tumor suppression can be achieved by this high‐yield oxygen‐producing biohybrid “microfactory” in a photodynamic/photothermal‐synergistic therapy strategy. Furthermore, Volbots also offer imaging capabilities and exhibit considerable promise as a multifunctional microrobotics‐based theranostic approach for a precision tumor therapy strategy.

How Do Bismuth-Based Nanomaterials Function as Promising Theranostic Agents for the Tumor Diagnosis and Therapy?

The complexity of the tumor microenvironment and the diversity of tumors seriously affect the therapeutic effect, the focus, therefore, has gradually been shifted from monotherapy to combination therapy in clinical research in order to improve the curative effect. The synergistic enhancement interactions among multiple monotherapies majorly contribute to the birth of the multi-mode cooperative therapy, whose effect of the treatment is clearly stronger than that of any single therapy. In addition, the accurate diagnosis of the tumour location is also crucial to the treatment. Bismuth-based nanomaterials (NMs) hold great properties as promising theranostic platforms based on their many unique features that include low toxicity, excellent photothermal conversion efficiency as well as the high ability of X-ray computed tomography imaging and photoacoustic imaging. In this review, we will introduce briefly the main features of the tumor microenvironment first and its effect on the mechanism of nanomedicine actions and present the recent advances of bismuth-based NMs for diagnosis and photothermal therapy-based combined therapies using bismuth-based NMs are presented, which may provide a new way for overcoming drug resistance and hypoxia. In the end, further challenges and outlooks regarding this promising field are discussed accompanied with some design tips for bismuth- based NMs, hoping to provide researchers some inspiration to design safe and effective nanotherapeutic agents for clinical treatments of cancers.