Bacteria-Based Backpacks to Enhance Adoptive Macrophage Transfer against Solid Tumors.

Adoptive cell therapy has emerged as a promising approach for cancer treatment. However, the transfer of macrophages exhibits limited efficacy against solid tumors due to the dynamic cellular phenotypic shift from antitumor to protumor states within the immunosuppressive tumor microenvironment. In this study, a strategy of attaching bacteria to macrophages (Mø@bac) is reported that endows adoptively infused macrophages with durable stimulation by leveraging the intrinsic immunogenicity of bacteria. These attached bacteria, referred to as backpacks, are encapsulated with adhesive nanocoatings and can sustainably control the cellular phenotypes in vivo. Moreover, Mø@bac can repolarize endogenous tumor-associated macrophages, leading to a more robust immune response and thus reducing the tumor progression in a murine 4T1 cancer model without any side effects. This study utilizing bacteria as cellular backpacks opens a new avenue for the development of cell therapies.

Dendritic Cell-Based In Situ Nanovaccine for Reprogramming Lipid Metabolism to Boost Tumor Immunotherapy.

Cancer vaccines have been considered to be an alternative therapeutic strategy for tumor therapy in the past decade. However, the popularity and efficacy of cancer vaccines were hampered by tumor antigen heterogeneity and the impaired function of cross-presentation in the tumor-infiltrating dendritic cells (TIDCs). To overcome these challenges, we engineered an in situ nanovaccine (named as TPOP) based on lipid metabolism-regulating and innate immune-stimulated nanoparticles. TPOP could capture tumor antigens and induce specific recognition by TIDCs to be taken up. Meanwhile, TPOP could manipulate TIDC lipid metabolism and inhibit de novo synthesis of fatty acids, thus improving the ability of TIDCs to cross-present by reducing their lipid accumulation. Significantly, intratumoral injection of TPOP combined with pretreatment with doxorubicin showed a considerable therapeutic effect in the subcutaneous mouse colorectal cancer model and melanoma model. Moreover, in combination with immune checkpoint inhibitors, such TPOP could markedly inhibit the growth of distant tumors by systemic antitumor immune responses. This work provides a safe and promising strategy for improving the function of immune cells by manipulating their metabolism and activating the immune system effectively for in situ cancer vaccines.

Tuning Bacterial Morphology to Enhance Anticancer Vaccination.

Morphology tuning is a potent strategy to modulate physiological effects of synthetic biomaterials, but it is rarely explored in microbe-based biochemicals due to the lack of artificial adjustability. Inspired by the interesting phenomenon of microbial transformation, Escherichia coli is rationally adjusted into filamentous morphology-adjusted bacteria (MABac) via chemical stimulation to prepare a bacteria-based vaccine adjuvant/carrier. Inactivated MABac display stronger immunogenicity and special delivery patterns (phagosome escape and cytoplasmic retention) that are sharply distinct from the short rod-shaped bacteria parent (Bac). Transcriptomic study further offers solid evidence for deeply understanding the in vivo activity of MABac-based vaccine, which more effectively motivates multiple cytosolic immune pathways (such as NOD-like receptors and STING) and induces pleiotropic immune responses in comparison with Bac. Harnessing the special functions caused by morphology tuning, the MABac-based adjuvant/carrier significantly improves the immunogenicity and delivery profile of cancer antigens in vivo, thus boosting cancer-specific immunity against the melanoma challenge. This study validates the feasibility of tuning bacterial morphology to improve their biological effects, establishing a facile engineering strategy that upgrades bacterial properties and functions without complex procedures like gene editing.

Homotypic Targeted Photosensitive Nanointerferer for Tumor Cell Cycle Arrest to Boost Tumor Photoimmunotherapy.

Recent advances in tumor immunotherapy mainly tend to remodel the immunosuppressive tumor microenvironment (TME) for immune enhancement. However, the complexity of TME makes it unlikely to achieve satisfactory therapeutic effects with any single intervention alone. Here, we focus on exposing intrinsic features of tumor cells to trigger direct pleiotropic antitumor immunity. We develop a photosensitive nanointerferer that is engineered with a nanoscale metal-organic framework decorated with tumor cell membranes for targeted delivery of a photosensitizer and small interfering RNA, which is used to knock down cyclin-dependent kinase 4 (Cdk4). Cdk4 blockade can arrest the cell cycle of tumor cells to facilitate antigen exposure and increase the expression level of programmed cell death protein ligand 1 (PD-L1). Under laser irradiation, photodynamic damage triggered by the nanointerferer induces the release of tumor antigens and recruitment of dendritic cells (DCs), thereby promoting the antitumor activity of CD8+ T cells in combination with anti-PD-L1 antibodies. Ultimately, these events markedly retard tumor progression in a mouse model of ectopic colon tumor with negligible adverse effects. This study provides an alternative treatment for effective antitumor immunity by exciting the intrinsic potential of tumor cells to initiate immune responses while reducing immune-related toxicities.

Hybrid suture coating for dual-staged control over antibacterial actions to match well wound healing progression.

Absorbable sutures have moved to the forefront in surgical fields with a huge market. Antibacterial activity is one indispensable feature for the next generation of absorbable sutures. This study develops a simple and cost-effective coating method to endow sutures with staged control over antibacterial actions to achieve enhanced dual stages of the wound healing process. This method is achieved in aqueous solution under mild conditions without the usage of any organic solvent and reserves the fundamental properties of suture materials, based on the pH-dependent reversible self-polymerization of tannic acid (TA) together with the strong adhesion of poly (tannic acid) (PTA) not only toward the suture surface but also with TA. Just by changing pH of TA solution, a hybrid coating (MPTA) composed of PTA and TA could be readily formed on the commercialized sutures originating from synthetic and natural materials. In the initial post-surgery stage, wound sites are susceptible to aseptic and/or bacterial inflammation. The resulting acid conditions induce burst release of antibacterial TA mostly coming from the adsorbed TA monomer. In the later stage, TA release is tailored totally depending on the pH conditions determined by the healing degree of wounds, allowing the sustained antibacterial prevention in a biologically adjustable manner. Thus, antibacterial MPTA coating meets the rigid requirements that differ distinctly during two major wound healing stages. Nontoxic MPTA coating on sutures leads to excellent post-implantation outcomes regarding bacterial prevention/elimination, anti-inflammation, tissue repair and wound healing. Moreover, MPTA coating provides sutures with a robust platform for functional expansion due to the matrix-independent adhesive ability of PTA.

Temulence Therapy to Orthotopic Colorectal Tumor via Oral Administration of Fungi-Based Acetaldehyde Generator.

Taking inspiration from percutaneous ethanol injection (PEI) for tumor ablation, an acetaldehyde generator (SC@ZIF@ADH) is constructed for tumor treatment by modifying a metal-organic framework nanocarrier (ZIF), which is loaded with alcohol dehydrogenase (ADH), onto the surface of Saccharomyces cerevisiae (SC). Oral administration of SC@ZIF@ADH can target tumor via mannose-mediated targeting to tumor associated macrophages (TAMs) and generate ethanol at the hypoxic tumor areas. Ethanol is subsequently catalyzed to toxic acetaldehyde by ADH, inducing tumor cells apoptosis and polarizing TAMs toward the anti-tumor phenotype. In vivo animal results show that this acetaldehyde generator can cause a temulence-like reaction in the tumor, significantly inhibiting tumor progression, and might provide an intelligent and nonsurgical substitute for PEI therapy.

Nanocatalyst-Mediated Chemodynamic Tumor Therapy.

Traditional tumor treatments, including chemotherapy, radiotherapy, photodynamic therapy, and photothermal therapy, are developed and used to treat different types of cancer. Recently, chemodynamic therapy (CDT) has been emerged as a novel cancer therapeutic strategy. CDT utilizes Fenton or Fenton-like reaction to generate highly cytotoxic hydroxyl radicals (•OH) from endogenous hydrogen peroxide (H2 O2 ) to kill cancer cells, which displays promising therapeutic potentials for tumor treatment. However, the low catalytic efficiency and off-target side effects of Fenton reaction limit the biomedical application of CDT. In this regard, various strategies are implemented to potentiate CDT against tumor, including retrofitting the tumor microenvironment (e.g., increasing H2 O2 level, decreasing reductive substances, and reducing pH), enhancing the catalytic efficiency of nanocatalysts, and other strategies. This review aims to summarize the development of CDT and summarize these recent progresses of nanocatalyst-mediated CDT for antitumor application. The future development trend and challenges of CDT are also discussed.

Transformable Spinose Nanodrums with Self-Supplied H2 O2 for Photothermal and Cascade Catalytic Therapy of Tumor.

Advances in enzymes involve an efficient biocatalytic process, which has demonstrated great potential in biomedical applications. However, designing a functional carrier for enzymes equipped with satisfactory degradability and loading efficiency, remains a challenge. Here, based on transformable liquid metal (LM), a spinose nanodrum is designed as protein carrier to deliver enzyme for tumor treatment. With the assistance of spines and a special drum-like shape, it is found that the spiny LM can carry much more enzymes than spherical LM under the same condition. Benefiting from the satisfactory enzyme loading efficiency of spiny LM, a plasma amine oxidase immobilized spinose LM nanosystem enveloped with epigallocatechin gallate (EGCG)-Fe3+ (LMPE) is fabricated for photothermal and cascade catalytic tumor therapy. Activated by the acidic condition in the tumor microenvironment, the LMPE can oxidize spermine (Spm) and spermidine (Spd) to generate hydrogen peroxide (H2 O2 ) for Fenton catalytic reaction to produce the lethal hydroxyl radical (•OH) for tumor cell killing. Combined with remarkable photothermal performance of LM, LMPE exhibits significant inhibition of tumor in vivo.

A near infrared ratiometric platform based π-extended porphyrin metal-organic framework for O2 imaging and cancer therapy.

Photodynamic therapy (PDT) is widely researched in tumor treatment, but its therapeutic effect is affected by oxygen (O2) concentration of tumor site. Here, we developed a Pd-coordinated π-conjugated extended porphyrin doped porphyrin metal-organic-framework (named as PTP). PTP can achieve near infrared (NIR) O2 concentration ratiometric imaging, solving the problems of short detection wavelengths and influence of self-concentrations. With the NIR excitation wavelength and the ability of higher singlet oxygen (1O2) generation, PTP can induce PDT more effectively. The efficient PDT also mediates cancer immunogenic cell death (ICD), which combines with the immune checkpoint inhibitor αPD-1 to achieve obviously cancer suppression and anti-metastasis effect. This theranostic NIR ratiometric nanoprobe can be used as a pre-evaluation on the outcome of PDT and high-efficient cancer combined treatment system, which will find great potential in tumor diagnosis and treatment.

Integration of a porous coordination network and black phosphorus nanosheets for improved photodynamic therapy of tumor.

Selectively attenuating the protection offered by heat shock protein 90 (HSP90), which is indispensable for the stabilization of the essential regulators of cell survival and works as a cell guardian under oxidative stress conditions, is a potential approach to improve the efficiency of cancer therapy. Here, we designed a biodegradable nanoplatform (APCN/BP-FA) based on a Zr(iv)-based porphyrinic porous coordination network (PCN) and black phosphorus (BP) sheets for efficient photodynamic therapy (PDT) by enhancing the accumulation of the nanoplatforms in the tumor area and attenuating the protection of cancer cells. Owing to the favorable degradability of BP, the nanosystem exhibited accelerated the release of the HSP90 inhibitor tanespimycin (17-AAG) and an apparent promotion in the reactive oxygen species (ROS) yield of PCN as well as expedited the degradation of the PCN-laden BP nanoplatforms. Both in vitro and in vivo results revealed that the elevated amounts of ROS and reduced cytoprotection in tumor cells were caused by the nanoplatforms. This strategy may provide a promising method for attenuating cytoprotection to aid efficient photodynamic therapy.

Nitric Oxide Release Device for Remote-Controlled Cancer Therapy by Wireless Charging.

Traditional phototherapies face the issue that the insufficient penetration of light means it is difficult to reach deep lesions, which greatly reduces the feasibility of cancer therapy. Here, an implantable nitric oxide (NO)-release device is developed to achieve long-term, long-distance, remote-controllable gas therapy for cancer. The device consists of a wirelessly powered light-emitting diode (wLED) and S-nitrosoglutathione encapsulated with poly(dimethylsiloxane) (PDMS), obtaining the NO-release wLED (NO-wLED). It is found that NO release from the NO-wLED can be triggered by wireless charging and the concentration of produced NO reaches 0.43 × 10-6 m min-1 , which can achieve a killing effect on cancer cells. In vivo anticancer experiments exhibit obvious inhibitory effect on the growth of orthotopic cancer when the implanted NO-wLED is irradiated by wireless charging. In addition, recurrence of cancer can be prevented by NO produced from the NO-wLED after surgery. By illumination in the body, this strategy overcomes the poor penetration and long-wavelength dependence of traditional phototherapies, which also provides a promising approach for in vivo gas therapy remote-controlled by wireless charging.

Platelet-Mimicking Biotaxis Targeting Vasculature-Disrupted Tumors for Cascade Amplification of Hypoxia-Sensitive Therapy.

Tumorous vasculature plays key roles in sustaining tumor growth. Vascular disruption is accompanied by internal coagulation along with platelet recruitment and the resulting suppression of oxygen supply. We intend to artificially create this physiological process to establish the mutual feedback between vascular disruption and platelet-mimicking biotaxis for the cascade amplification of hypoxia-dependent therapy. To prove this concept, mesoporous silica nanoparticles are co-loaded with a hypoxia-activated prodrug (HAP) and a vessel-disruptive agent and then coated with platelet membranes. Upon entering into tumors, our nanotherapeutic can disrupt local vasculature for tumor inhibition. This platelet membrane-coated nanoplatform shares the hemorrhage-tropic function with parental platelets and can be persistently recruited by the vasculature-disrupted tumors. In this way, the intratumoral vascular disruption and tumor targeting are biologically interdependent and mutually reinforced. Relying on this mutual feedback, tumorous hypoxia was largely promoted by more than 20-fold, accounting for the effective recovery of the HAP's cytotoxicity. Consequently, our bioinspired nanodesign has demonstrated highly specific and effective antitumor potency via the biologically driven cooperation among intratumoral vascular disruption, platelet-mimicking biotaxis, cascade hypoxia amplification, and hypoxia-sensitive chemotherapy. This study offers a paradigm of correlating the therapeutic design with the physiologically occurring events to achieve better therapy performance.

Cytomembrane-Mediated Transport of Metal Ions with Biological Specificity.

Metal ions are of significant importance in biomedical science. This study reports a new concept of cytomembrane-mediated biospecific transport of metal ions without using any other materials. For the first time, cytomembranes are exploited for two-step conjugation with metal ions to provide hybrid nanomaterials. The innate biofunction of cell membranes renders the hybrids with superior advantages over common vehicles for metal ions, including excellent biocompatibility, low immunogenic risk, and particularly specific biotargeting functionality. As a proof-of-concept demonstration, cancer cell membranes are used for in vivo delivery of various metal ions, including ruthenium, europium, iron, and manganese, providing a series of tumor-targeted nanohybrids capable of photothermal therapy/imaging, magnetic resonance imaging, photoacoustic imaging, and fluorescence imaging with improved performances. In addition, the special structure of the cell membrane allows easy accommodation of small-molecular agents within the nanohybrids for effective chemotherapy. This study provides a new class of metal-ion-included nanomaterials with versatile biofunctions and offers a novel solution to address the important challenge in the field of in vivo targeted delivery of metal ions.

Hydrogen gas improves photothermal therapy of tumor and restrains the relapse of distant dormant tumor.

Inflammation during photothermal therapy (PTT) of tumor usually results in adverse consequences. Here, a biomembrane camouflaged nanomedicine (mPDAB) containing polydopamine and ammonia borane was designed to enhance PTT efficacy and mitigate inflammation. Polydopamine, a biocompatible photothermal agent, can effectively convert light into heat for PTT. Ammonia borane was linked to the surface of polydopamine through the interaction of hydrogen bonding, which could destroy redox homoeostasis in tumor cells and reduce inflammation by H2 release in tumor microenvironment. Owing to the same origin of outer biomembranes, mPDAB showed excellent tumor accumulation and low systemic toxicity in a breast tumor model. Excellent PTT efficacy and inflammation reduction made the mPDAB completely eliminate the primary tumors, while also restraining the outgrowth of distant dormant tumors. The biomimetic nanomedicine shows potentials as a universal inflammation-self-alleviated platform to ameliorate inflammation-related disease treatment, including but not limited to PTT for tumor.

Cytomembrane nanovaccines show therapeutic effects by mimicking tumor cells and antigen presenting cells.

Most cancer vaccines are unsuccessful in eliciting clinically relevant effects. Without using exogenous antigens and adoptive cells, we show a concept of utilizing biologically reprogrammed cytomembranes of the fused cells (FCs) derived from dendritic cells (DCs) and cancer cells as tumor vaccines. The fusion of immunologically interrelated two types of cells results in strong expression of the whole tumor antigen complexes and the immunological co-stimulatory molecules on cytomembranes (FMs), allowing the nanoparticle-supported FM (NP@FM) to function like antigen presenting cells (APCs) for T cell immunoactivation. Moreover, tumor-antigen bearing NP@FM can be bio-recognized by DCs to induce DC-mediated T cell immunoactivation. The combination of these two immunoactivation pathways offers powerful antitumor immunoresponse. Through mimicking both APCs and cancer cells, this cytomembrane vaccine strategy can develop various vaccines toward multiple tumor types and provide chances for accommodating diverse functions originating from the supporters.

Immobilized liquid metal nanoparticles with improved stability and photothermal performance for combinational therapy of tumor.

Various negative effects accompanying with the instability of bare liquid metal (LM) nanoparticles, including undesirable spontaneous coalescence, continuous photothermal performance deterioration and difficult multi-step functionalization, severely hinder its applications in biomedical area. In this study, we proposed a new concept of immobilized liquid metal nanoparticles based on a surface mesoporous silica coating strategy (LM@MSN). Strikingly, it was found that unsteady and vulnerable LM nanoparticles after immobilization exhibited enhanced stabilization and sustainable photothermal performance even with a long and repeated light irradiation in acidic environments. Moreover, integrating the properties of easy surface functionalization and high drug loading efficiency from silica shell, immobilized LM nanoparticle was further used for photothermal involved combinational therapy. The classical anticancer drug doxorubicin (DOX) was encapsulated in pores of silica shell and the hyaluronic acid (HA) was decorated on LM@MSN to construct LM@MSN/DOX@HA for tumor targeted combination therapy. Both in vitro and in vivo studies proved that LM@MSN/DOX@HA could significantly inhibit solid tumor growth under near infrared (NIR) irradiation by synergistic photothermal/chemotherapy.

Expandable Immunotherapeutic Nanoplatforms Engineered from Cytomembranes of Hybrid Cells Derived from Cancer and Dendritic Cells.

Using the cytomembranes (FMs) of hybrid cells acquired from the fusion of cancer and dendritic cells (DCs), this study offers a biologically derived platform for the combination of immunotherapy and traditional oncotherapy approaches. Due to the immunoactivation implicated in the cellular fusion, FMs can effectively express whole cancer antigens and immunological co-stimulatory molecules for robust immunotherapy. FMs share the tumor's self-targeting character with the parent cancer cells. In bilateral tumor-bearing mouse models, the FM-coated nanophotosensitizer causes durable immunoresponse to inhibit the rebound of primary tumors post-nanophotosensitizer-induced photodynamic therapy (PDT). The FM-induced immunotherapy displays ultrahigh antitumor effects even comparable to that of PDT. On the other hand, PDT toward primary tumors enhances the immunotherapy-caused regression of the irradiation-free distant tumors. Consequently, both the primary and the distant tumors are almost completely eliminated. This tumor-specific immunotherapy-based nanoplatform is potentially expandable to multiple tumor types and readily equipped with diverse functions owing to the flexible nanoparticle options.

Engineered Bacterial Bioreactor for Tumor Therapy via Fenton-Like Reaction with Localized H2 O2 Generation.

Synthetic biology based on bacteria has been displayed in antitumor therapy and shown good performance. In this study, an engineered bacterium Escherichia coli MG1655 is designed with NDH-2 enzyme (respiratory chain enzyme II) overexpression (Ec-pE), which can colonize in tumor regions and increase localized H2 O2 generation. Following from this, magnetic Fe3 O4 nanoparticles are covalently linked to bacteria to act as a catalyst for a Fenton-like reaction, which converts H2 O2 to toxic hydroxyl radicals (•OH) for tumor therapy. In this constructed bioreactor, the Fenton-like reaction occurs with sustainably synthesized H2 O2 produced by engineered bacteria, and severe tumor apoptosis is induced via the produced toxic •OH. These results show that this bioreactor can achieve effective tumor colonization, and realize a self-supplied therapeutic Fenton-like reaction without additional H2 O2 provision.

Artificially Reprogrammed Macrophages as Tumor-Tropic Immunosuppression-Resistant Biologics to Realize Therapeutics Production and Immune Activation.

To engineer patient-derived cells into therapy-purposed biologics is a promising solution to realize personalized treatments. Without using gene-editing technology, a live cell-typed therapeutic is engineered for tumor treatment by artificially reprogramming macrophages with hyaluronic acid-decorated superparamagnetic iron oxide nanoparticles (HIONs). This nanoparticle-assisted cell-reprogramming strategy demonstrates profound advantages, due to the combined contributions from the biological regulation of HIONs and the intrinsic nature of macrophages. Firstly, the reprogrammed macrophages present a substantial improvement in their innate capabilities, such as more effective tumor targeting and more efficient generation of bioactive components (e.g., reactive oxygen species, bioactive cytokines) to suppress tumor growth. Furthermore, this cell therapeutic exhibits cytostatic/proapoptotic effects specific to cancer cells. Secondly, HIONs enable macrophages more resistant to the intratumoral immunosuppressive environment. Thirdly, the macrophages are endowed with a strong ability to prime in situ protumoral M2 macrophages into antitumor M1 phenotype in a paracrine-like manner. Consequently, a synergistic tumor-inhibition effect is achieved. This study shows that engineering nanomaterial-reprogrammed live cells as therapeutic biologics may be a more preferable option to the commonly used approaches where nanomaterials are administrated to induce bioresponse of certain cells in vivo.

O2 Economizer for Inhibiting Cell Respiration To Combat the Hypoxia Obstacle in Tumor Treatments.

Hypoxia, a ubiquitously aberrant phenomenon implicated in tumor growth, causes severe tumor resistance to therapeutic interventions. Instead of the currently prevalent solution through intratumoral oxygen supply, we put forward an "O2-economizer" concept by inhibiting the O2 consumption of cell respiration to spare endogenous O2 and overcome the hypoxia barrier. A nitric oxide (NO) donor responsible for respiration inhibition and a photosensitizer for photodynamic therapy (PDT) are co-loaded into poly(d,l-lactide- co-glycolide) nanovesicles to provide a PDT-specific O2 economizer. Once accumulating in tumors and subsequently responding to the locally reductive environment, the carried NO donor undergoes breakdown to produce NO for inhibiting cellular respiration, allowing more O2 in tumor cells to support the profound enhancement of PDT. Depending on the biochemical reallocation of cellular oxygen resource, this O2-economizer concept offers a way to address the important issue of hypoxia-induced tumor resistance to therapeutic interventions, including but not limited to PDT.