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Micro-nano biorobots based on bacteria have demonstrated great potential for tumor diagnosis and treatment. The bacterial gene expression and drug release should be spatiotemporally controlled to avoid drug release in healthy tissues and undesired toxicity. Herein, we describe an alternating magnetic field-manipulated tumor-homing bacteria developed by genetically modifying engineered Escherichia coli with Fe 3 O 4 @lipid nanocomposites. After accumulating in orthotopic colon tumors in female mice, the paramagnetic Fe 3 O 4 nanoparticles enable the engineered bacteria to receive and convert magnetic signals into heat, thereby initiating expression of lysis proteins under the control of a heat-sensitive promoter. The engineered bacteria then lyse, releasing its anti-CD47 nanobody cargo, that is pre-expressed and within the bacteria. The robust immunogenicity of bacterial lysate cooperates with anti-CD47 nanobody to activate both innate and adaptive immune responses, generating robust antitumor effects against not only orthotopic colon tumors but also distal tumors in female mice. The magnetically engineered bacteria also enable the constant magnetic field-controlled motion for enhanced tumor targeting and increased therapeutic efficacy. Thus, the gene expression and drug release behavior of tumor-homing bacteria can be spatiotemporally manipulated in vivo by a magnetic field, achieving tumor-specific CD47 blockage and precision tumor immunotherapy. Several strategies have been employed to enhance the tumor-targeting and anti-cancer properties of engineered bacteria. Here the authors describe the design of alternating magnetic field-manipulated bacteria engineered to release an anti-CD47 nanobody, promoting anti-tumor immune response in preclinical cancer models.

Oral vaccines provide a non-invasive approach for cancer immunotherapy but face challenges in gastrointestinal stability, antigen presentation, and mucosal delivery. Here, we present an engineered probiotic-based oral vaccine system, Bac OR-Fn-T+phiX174 , featuring genetically encoded dual-antigen ferritin arrays and inducible bacterial lysis. Upon oral administration and arabinose induction, the probiotic strain lyses in situ, releasing OVA/TRP2-decorated ferritin nanoparticles that efficiently traverse the intestinal barrier via M-cell targeting and activate mucosal dendritic cells. This platform robustly stimulates CD8 + and CD4 + T-cell responses, enhances B-cell and macrophage activation, reduces regulatory T cells, and provides therapeutic efficacy against melanoma in both lung metastasis and subcutaneous tumor models. It also establishes durable immunological memory without disrupting systemic or mucosal homeostasis. This work offers a programmable bacterial chassis for precise antigen array presentation and controlled delivery, representing a promising strategy for next-generation, needle-free cancer vaccines. Minimally invasive oral vaccine delivery is a desired approach. Here, the authors report on an engineered probiotic-based oral vaccine system that enables controlled mucosal delivery of ferritin-displayed dual antigens, eliciting robust mucosal and systemic antitumor immune responses.

The limited efficacy of radiotherapy leads to radio‐resistance and high rates of tumor recurrence and metastasis, which is caused by tumor hypoxia, rapid DNA damage repair, and especially the suppressive immune microenvironment of tumor. Lots of immune cell‐derived exosomes can regulate antitumor immunity, but their application in enhancing radiotherapy is rarely studied. Herein, as a model of concept, M1 macrophage‐derived exosomes (M1Exos) is engineered as effective radiotherapy sensitizers, realizing the trilogy of radiotherapy sensitization: 1) M1Exos is engineered to express catalases on the inside of membrane, which can effectively relieve tumor hypoxia, and enhance DNA damage. 2) The DNA damage repair inhibitor is loaded in M1Exos to effectively inhibit DNA damage repair. 3) M1Exos can polarize M2 macrophages into M1 phenotypes, and the anti‐PD‐L1 nanobody engineered on the outside of M1Exos can relieve the immunosuppression of T cells, both ultimately leading to the remodeling of the tumor suppressive microenvironment. The trilogy of radiotherapy sensitization achieves excellent antitumor efficacy, exhibiting the good utility of engineering immune cell‐derived exosomes as radiotherapy sensitizers, inspiring the future efforts to explore different kinds of immune cell‐derived exosomes for enhanced radiotherapy. M1 macrophage‐derived exosomes with catalase (CAT) and anti‐PD‐L1 (programmed death ligand‐1) nanobody expressed on membrane and DNA damage repair inhibitor (DDRi) encapsulated inside is engineered as effective radiotherapy sensitizers, realizing the trilogy of radiotherapy sensitization: the relief of tumor hypoxia, the inhibition of DNA damage repair, and the remodeling of tumor suppressive immune microenvironment. This work exhibits the good utility of engineering immune cell‐derived exosomes as effective radiotherapy sensitizers.

Photothermal therapy (PTT) mediated by nanomaterial has become an attractive tumor treatment method due to its obvious advantages. Among various nanomaterials, melanin-like nanoparticles with nature biocompatibility and photothermal conversion properties have attracted more and more attention. Melanin is a natural biological macromolecule widely distributed in the body and displays many fascinating physicochemical properties such as excellent biocompatibility and prominent photothermal conversion ability. Due to the similar properties, Melanin-like nanoparticles have been extensively studied and become promising candidates for clinical application. In this review, we give a comprehensive introduction to the recent advancements of melanin-like nanoparticles in the field of photothermal therapy in the past decade. In this review, the synthesis pathway, internal mechanism and basic physical and chemical properties of melanin-like nanomaterials are systematically classified and evaluated. It also summarizes the application of melanin-like nanoparticles in bioimaging and tumor photothermal therapy (PTT)in detail and discussed the challenges they faced in clinical translation rationally. Overall, melanin-like nanoparticles still have significant room for development in the field of biomedicine and are expected to applied in clinical PTT in the future.

Chemotherapy remains one of the irreplaceable treatments for cancer therapy. The use of immunogenic cell death (ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells, simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B (GrB). However, numerous malignant cancers adaptively acquired the capacity of secreting serpinb9 (Sb9), a physiological inhibitor of GrB, which can reversibly inhibit the biological activity of GrB. To circumvent this dilemma, in this study, an integrated tailor-made nanomedicine composed of tumor-targeting peptide (Arg-Gly-Asp, RGD) decorated liposome, doxorubicin (DOX, an effective ICD inducer), and the compound 3034 (an inhibitor of Sb9), is developed (termed as D3RL) for breast cancer chemo-immunotherapy. In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD. Meanwhile, D3RL can competitively relieve the inhibition of Sb9 to GrB. The restored GrB can not only effectively induce tumor immunotherapy, but also degrade matrix components in the tumor microenvironment, consequently improving the infiltration of immune cells and the penetration of nanomedicines, which in return enhance the combined antitumor effect. Taken together, this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemoimmunotherapy for breast cancer.

Trained immunity enhances the responsiveness of immune cells to subsequent infections or vaccinations. Here we demonstrate that pre-vaccination with bacteria-derived outer-membrane vesicles, which contain large amounts of pathogen-associated molecular patterns, can be used to potentiate, and enhance, tumour vaccination by trained immunity. Intraperitoneal administration of these outer-membrane vesicles to mice activates inflammasome signalling pathways and induces interleukin-1β secretion. The elevated interleukin-1β increases the generation of antigen-presenting cell progenitors. This results in increased immune response when tumour antigens are delivered, and increases tumour-antigen-specific T-cell activation. This trained immunity increased protection from tumour challenge in two distinct cancer models. The level of immune response in cancer vaccines can limit application. Here, an immune mobilization strategy, using bacteria-derived nanovesicles, enhances therapeutic outcomes of tumour vaccination by stimulating interleukin-1β secretion to elicit trained immunity with lineage shifts and epigenetic changes in myeloid progenitor pools.

The complex gastrointestinal environment and the intestinal epithelial barrier constrain the design and effectiveness of orally administered tumour vaccines. Here we show that outer membrane vesicles (OMVs) fused to a tumour antigen and produced in the intestine by ingested genetically engineered bacteria function as effective tumour vaccines in mice. We modified Escherichia coli to express, under the control of a promoter induced by the monosaccharide arabinose, a specific tumour antigen fused with the protein cytolysin A on the surface of OMVs released by the commensal bacteria. In mice, oral administration of arabinose and the genetically engineered E. coli led to the production of OMVs that crossed the intestinal epithelium into the lamina propria, where they stimulated dendritic cell maturation. In a mouse model of pulmonary metastatic melanoma and in mice bearing subcutaneous colon tumours, the antigen-bearing OMVs inhibited tumour growth and protected the animals against tumour re-challenge. The in situ production of OMVs by genetically modified commensal bacteria for the delivery of stimulatory molecules could be leveraged for the development of other oral vaccines and therapeutics. Tumour vaccines consisting of outer membrane vesicles bearing a specific tumour antigen and produced in the intestine by ingested genetically engineered bacteria generate long-term antitumour immunity in mice.

Traditional surgical treatment is difficult to thoroughly remove esophageal squamous cell carcinomas (ESCC), and postoperative recurrence caused by residual tumor cells is a critical factor in the poor prognosis. Since surgical resection promotes the local angiogenesis at the tumor site, further exacerbating the proliferation and invasion of residual tumor cells, it is urgent to inhibit angiogenesis after surgery. Here, a functional peptide-based nanomedicine was obtained from peptide—drug conjugates, which are composed of a hydrophilic targeting motif (vascular endothelial growth factor family and their receptors (VEGFR) targeting peptide for anti-angiogenesis), and an ester-linked hydrophobic oridonin (ORI). The nanomedicine exhibits esterase-catalyzed disassembly and drug release, and significantly enhanced the anti-tumor efficacy of chemotherapeutics in a postoperative tumor recurrence model through synergistic anti-angiogenic strategies. This study provides an integrated solution for anti-angiogenesis-augmented chemotherapy and demonstrates the encouraging potential for postoperative treatment.

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