Targeting Intratumoral Bacteria for Cancer Nanotherapeutics

Abstract

Intratumoral microbiota has emerged as a key modulator of cancer progression and therapeutic response, significantly influencing treatment outcomes. Although conventional microbiome-modulating approaches such as antibiotic administration can enhance cancer treatment efficacy, they frequently lead to inconsistent therapeutic results and disrupt beneficial microbial communities. Nanotechnology, with its capacity for precise interactions at microscopic and molecular scales, offers a promising solution for selectively regulating tumor-associated microbiota and reshaping the tumor microenvironment. This review elucidates current knowledge by conducting a comprehensive analysis of the literature, with a focus on classifying the antibacterial mechanisms of nanotechnology against intratumoral bacteria into physical, chemical, and biological modalities, and further discusses the precision design of nanomaterials, therapeutic outcomes, and antimicrobial mechanisms within each modality. Furthermore, we discuss challenges in precise targeting and safety, examine the translational progress of nanotechnology-based antimicrobial strategies, and propose future directions for research and clinical application.

1. Introduction

Tumor microbiota comprises the microbial community within tumor tissue and its surrounding microenvironment, including bacteria, fungi, viruses, and other microorganisms. − Distinct from the microbiota in normal tissues, it extends beyond the tumor microenvironment and often exhibits a unique microbial composition profile. − Emerging research highlights the high heterogeneity of intratumoral microbiota, with specific microorganisms strongly linked to the pathogenesis of diverse malignancies. − For instance, Helicobacter pylori is a well-recognized key pathogenic factor in gastric carcinogenesis, promoting oncogenic transformation through chronic immune stimulation and pro-inflammatory cytokine release that induce genomic instability and mutagenesis. Certain gut microbiota metabolize dietary carcinogens into short-chain fatty acids, which may contribute to gut cancer development under specific conditions. Additionally, Bacteroides fragilis in tumors produces toxins that stimulate tumor cell proliferation and are closely linked to colon cancer progression. Moreover, tumor microbiota can influence tumor progression by modulating the tumor immune microenvironment. − Intratumoral bacteria can also facilitate distant organ metastasis and impair cancer treatment outcomes by promoting therapy resistance and reducing patient survival. ,−

To address this challenge, strategies targeting invasive intratumoral bacteria during cancer therapy are gaining traction. These include conventional antibiotics, synthetic antibacterial polymers, phage therapies, and innovative antimicrobial materials at the forefront of antipathogen technology.

This review comprehensively analyzes tumor-associated bacteria, their roles in tumor progression, and their impact on therapeutic outcomes, while systematically evaluating established strategies for managing intratumoral bacterial infections–with particular emphasis on nanotechnology-based approaches. Our analysis highlights cutting-edge studies utilizing nanoplatforms to potentiate cancer therapy through targeted manipulation of oncogenic bacteria and tumor microbiota, ultimately concluding with a critical appraisal of translational challenges and future research trajectories for microbiota-directed nanotherapeutics in oncology.

2. Role of Intratumoral Bacteria in Tumor Development

The involvement of bacteria in tumorigenesis and progression has attracted scientific interest since the 19th century when microbes were first detected in tumors. Historically constrained by low bacterial abundance and technical limitations, systematic study of tumor-associated bacteria proved challenging.

Recent technological advances now confirm their pivotal role in tumor development and progression. , Notably, the oral commensal Fusobacterium nucleatum (Fn) is enriched in tumors and strongly correlates with recurrence, metastasis, and poor prognosis. Zepeda-Rivera et al. identified a tumor-derived Fna C2 clade driving Fn enrichment in colorectal cancer (CRC). Separately, Cai et al. discovered S. xylosus promotes breast cancer lung metastasis in spontaneous tumor models, and demonstrated that antibiotic targeting of this bacterium suppresses metastasis while elucidating the mechanisms of bacteria-mediated tumor cell dissemination. Ma et al. further demonstrated that butyrate from tumor-associated Roseburia enhances subcutaneous tumor growth and drives lymph node metastasis in lung cancer.

Beyond direct tumor interactions, microbiota modulate carcinogenesis via microenvironment remodeling. Tan et al. linked the periodontal pathogen Porphyromonas gingivalis to accelerated pancreatic cancer progression in murine models, inducing neutrophil-dominated inflammation through enhanced chemotactic factor and elastase secretion. Gu et al. found that E. coli promotes lung metastasis through lactate-mediated immune modulation: bacterial lactic acid inhibits NF-κB signaling pathway via RIG-I, polarizing M2 macrophages and altering Tregs/CD8⁺. Noci et al. discovered that aerosolized administration of antibiotics can remodel the lung microbiota, reduce regulatory T cells, and enhance the activity of T cells and NK cells, thereby suppressing melanoma lung metastasis and improving chemotherapy efficacy.

Collectively, these findings underscore tumor-associated bacteria orchestrate cancer progression through diverse and sophisticated mechanisms, including direct cellular interactions, microenvironment reprogramming, and immune regulation, as summarized in Figure .

1.

Multifunctional roles of intratumoral bacteria in cancer progression and therapy. Schematic illustration depicts how intratumoral bacteria: ① promote primary tumor growth; ② inactivate chemotherapeutic agents and driving therapy resistance; ③ facilitate distant metastasis; and ④ foster an immunosuppressive microenvironment by inhibiting CD8⁺ T cells while concurrently promoting immunosuppressive cells like Tregs and M2 macrophages.

3. Impact of Intratumoral Bacteria on Cancer Treatment Response

The tumor microbiota critically modulates therapeutic responses to radiotherapy, chemotherapy, and immunotherapy. Substantial evidence demonstrates its profound impact on treatment efficacy through multiple mechanisms-including drug metabolism modulation, resistance pathway induction, and tumor microenvironment remodeling. This section examines the complex interplay between tumor microbiota and cancer therapies, and further discusses emerging strategies to modulate tumor microbiota for improved treatment outcomes. We have summarized published intratumoral bacterial species capable of promoting resistance to antitumor therapy and their corresponding mechanisms in Table .

1. Mechanisms of Bacterial Modulation in Tumor Therapy Resistance.

colorectal cancer	Clostridium scindens	suppression of T-cell responses via Ca2+ ATPase and Ca2+-NFAT2 signaling
colorectal cancer	Escherichia coli	promotion of M2 polarization via RIG-I lactylation and NF-κB
colorectal cancer	Escherichia coli	bacterial CDD-mediated drug inactivation
colorectal cancer	Escherichia coli	alteration of drug molecular structures
colorectal cancer	Fusobacterium nucleatum	induction of chemoresistance via BIRC3
colorectal cancer	Fusobacterium nucleatum	activation of autophagy
colorectal cancer	Fusobacterium nucleatum	impairment of T-cell infiltration
colorectal cancer	Peptostreptococcus anaerobius	promotion of immunosuppressive MDSC infiltration
colorectal cancer	Fusobacterium nucleatum	reduction of CD8+ T-cell trafficking
pancreatic cancer	Gammaproteobacteria	bacterial CDD-mediated drug inactivation
pancreatic cancer	M. hyorhinis	bacterial CDD-mediated drug inactivation
breast cancer	Pseudomonas aeruginosa	conferral of trastuzumab resistance via TGF-β/ErbB2 signaling
cervical cancer	Lactobacillus iners	dysregulation of lactate signaling drives resistance
nasopharyngeal cancer	Fusobacterium nucleatum	enhancement of mitochondrial fusion and ROS reduction to confer radiation damage
esophageal cancer	Streptococcus	modulation of the tumor microenvironment to impact immunotherapy
esophageal cancer	Helicobacter pylori	alteration of gut microbiome and immunotherapy response
esophageal cancer	Fusobacterium nucleatum	blockade of T-cell activity and induction of ATF3-dependent PD-L1 expression

3.1. Radiotherapy and Chemotherapy

Tumor-resident bacteria significantly contribute to chemoresistance against widely used agents like gemcitabine. Bacterial cytidine deaminase (CDD) converts gemcitabine into inactive 2′,2′-difluorodeoxyuridine, driving tumor resistance. − Additional intratumoral microbiota inactivate chemotherapeutics through structural modifications or induce resistance mechanisms in CRC, including autophagy activation and anti-apoptotic factors upregulation. − These bacteria further compromise treatment by remodeling the tumor microenvironment or altering gut microbiota immune responses. ,

In breast cancer, Pseudomonas aeruginosa-derived quorum-sensing molecule 3oc promotes trastuzumab resistance via TGF-β receptor dimerization-induces ErbB2 phosphorylation, bypassing drug inhibition. Cervical tumor-associated lactic acid bacteria similarly drive chemotherapy resistance through metabolic reprogramming and lactate signaling, a phenomenon correlating with clinical outcomes beyond cervical tumors. Emerging evidence also highlights the role of Fn in radiotherapy resistance by enhancing mitochondrial fusion and reducing reactive oxygen species (ROS) production, thereby protecting tumor cells from radiation damage.

Collectively these studies demonstrate tumor-associated bacteria directly and indirectly modulate responses to radiotherapy and chemotherapy.

3.2. Immunotherapy

Gut and tumor-associated microbiota critically regulate immune responses and drive resistance to immune checkpoint inhibitors (ICIs). Despite the transformative impact of ICIs in enhancing antitumor immunity through targeting CTLA-4, PD-1, or PD-L1, their efficacy remains limited in many patients, in part due to immunosuppressive mechanisms driven by tumor-resident bacteria.

Fn contributes significantly to immunotherapy resistance. Its virulence factor Fn-Dps binds the PD-L1 promoter, activating ATF3 to upregulate PD-L1 and suppress T-cell function and diminish ICI efficacy. Fn also targets cancer cells via Fap2 agglutinin, which binds tumor Gal-GalNAc while simultaneously engaging inhibitory immune receptors to facilitate immune evasion. , Similarly, Porphyromonas anaerobius fosters CRC resistance by activating integrin α₂β₁/NF-κB signaling, recruiting CXCR2⁺ myeloid-derived suppressor cells, and enhancing immunosuppressive through lytC_22-Slamf4-mediated ARG1/iNOS upregulation.

Tumor-associated bacteria further impair dendritic cell function, reducing CD4⁺/CD8⁺ T-cell infiltration to create an immunologically “cold” microenvironment, which compromises immunotherapy outcomes. In CRC, Clostridium-derived deoxycholic acid inhibits CD8⁺ T-cell via Ca²⁺-nuclear factor of activated T cells -plasma membrane Ca²⁺ ATPase axis suppression, reducing IFN-γ/TNF-α production and facilitating tumor immune evasion. Fn-derived succinate similarly limits CD8⁺ T-cell infiltration and IFN-γ/TNF-α secretion, impairing T-cell/NK cell recruitment to tumors sites.

These bacteria exhibit context-dependent duality in cancer progression, functioning as “promoters” or “suppressors” based on abundance and microenvironment factors.

Their mechanistic roles highlight novel therapeutic targets for overcoming immune evasion. Future research should prioritize precise microbiota modulation, particularly nanotechnology-based approaches, to develop personalized cancer therapies.

4. Nanotechnology-Based Approaches

Conventional bacterial therapies for cancer, such as antibiotics, have long been constrained by nonspecific toxicity and, more critically, drug resistance. In recent years, the emergence of nanotechnology has introduced novel opportunities to overcome these limitations, enabling precise intratumoral targeting and the integration of multiple antimicrobial modalities. As summarized in Table , nanoplatforms offer distinct advantages over conventional antibiotics for intervening against intratumoral bacteria, including targeted delivery and synergistic antimicrobial mechanisms. As illustrated in Figure , this review provides a systematic overview of these nanoenabled strategies against tumor-associated bacteria, with particular emphasis on their underlying mechanisms and therapeutic applications.

2. Nanoplatforms vs. Conventional Antibiotics.

feature	nanoplatforms	antibiotics	ref
specificity	high; precise	low; broad-spectrum	,,
mechanism	multimodal & synergistic	singular & biochemical	,,
resistance	mitigates & overcomes	prone to induction	,
efficacy	potentiated & integrated	limited	,,
adaptability & design	highly programmable & tunable	fixed structure & function	,,

2.

Current nanoplatforms enable interventions against intratumoral bacteria through three primary antimicrobial mechanisms: physical, chemical, and biological damage.

4.1. Physical Damage Mechanisms

The mechano-bactericidal action of nanomaterials, which directly induces bacterial cell death through physical interactions such as membrane piercing and mechanical disruption, stands as a primary antimicrobial pathway. This potent physical mode of sterilization, which operates independently of chemical agents, offers the pivotal advantage of minimizing the risk of inducing bacterial resistance. Consequently, bioinspired nanostructured surfaces leveraging this mechanism have emerged as a profoundly promising strategy for constructing safe and effective antibacterial surfaces, attracting significant attention particularly in healthcare for mitigating surface contamination.

Beyond direct physical contact, the antimicrobial scope of nanomaterials extends to indirect physical mechanisms, wherein they act as agents for ROS generation via the photodynamic effect (PDT) or induce localized hyperthermia via the photothermal effect (PTT).

These light-driven reactions lead to oxidative and thermal damageprocesses initiated by the nanomaterials but ultimately executed through chemical or thermal pathways, underscoring their great research importance for advancing sterile medical devices.

4.1.1. Bacterial Cell Membrane Destruction

Leveraging their ultrasmall size and high surface-area-to-volume ratio, nanomaterials exhibit potent bactericidal activity through direct physical interactions with bacterial membranes. A key mechanism involves mechano-bactericidal effects, driven by intrinsic nanomaterial properties such as rigidity, toughness, and elasticity. Additionally, electrostatic attraction facilitates the binding of positively charged nanomaterials to negatively charged bacterial surfaces, resulting in membrane disruption, permeabilization, and eventual cell lysis. Together, these strategies underscore the multifaceted potential of nanomaterials in combating bacterial infections via direct physical pathways.

Zhang et al. invented a hybrid nanopillar system where the primary bactericidal mechanism is the physical rupture of bacterial cell membranes. They fabricated cicada-wing-inspired polymeric nanopillars via an anodized aluminum oxide template-assisted method and subsequently functionalized them with a tannic acid/iron ion (TA/Fe^{3 +}) complex through layer-by-layer assembly. The underlying nanopillars mechanically penetrate and disrupt bacterial cells upon contact, while the TA/Fe^{3 +} coating provides a supplementary photothermal effect that softens the rigid cell walls of Gram-positive bacteria under NIR irradiation, thereby facilitating more efficient mechanical destruction (Figure A). This synergistic approach achieved remarkable bactericidal efficiency exceeding 99% against both Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus, while maintaining excellent biocompatibility with mammalian cells due to the selective action of the physical mechanism.

3.

Mechano-bactericidal action via physical membrane disruption. (A) Antibacterial mechanism of TA/Fe@Polymer hybrid nanopillars upon NIR irradiation. Reproduced with permission from ref , Copyright 2023, Elsevier. (B) Antibacterial mechanism of Ag/QAs-MSNs. Reproduced with permission from ref , Copyright 2022, Frontiers Media S.A. (C) SEM images of (a, b) VACNTs with different heights (1 and 30 μm), and (c, d) deformed S. aureus and P. aeruginosa on VACNTs. Scale bars: 1 μm. Reproduced with permission from ref , Copyright 2018, American Chemical Society. (D) Confocal laser scanning microscopy images of live (green)/dead (red) bacteria on (a) silicon wafer, (b) ZnO nanopillars, and (c–e) PNIPAAm@ZnO surfaces (insets: viability percentages); (f) bacterial coverage statistics; (g–i) schematics of bacterium–surface interactions on PNIPAAm@ZnO-1 to −3. Reproduced with permission from ref , Copyright 2021, American Chemical Society. (E) Schematic of the bioinspired nanopillar surface. (a) preparation process. (b) Bacterial killing and releasing mechanism of the bioinspired nanopillar surface. Reproduced with permission from ref , Copyright 2022, Elsevier.

In a related effort to combine multiple antibacterial modalities, another study by Zhang et al. reported the synthesis of Ag and quaternary ammonium salt (QAS) cofunctionalized mesoporous silica nanoparticles (Ag/QAS-MSNs) for synergistic cancer and bacterial treatment. The proposed antibacterial mechanism involves multiple stages: first, electrostatic adhesion of positively charged nanoparticles to the bacterial membrane causes initial damage; second, sustained release of Ag⁺ ions and QAS induces extensive membrane disruption and cell death (Figure B); and third, Ag⁺-generated reactive oxygen species promote membrane lipid peroxidation, DNA damage, and protein denaturation. The combined physical and chemical actions result in potent antibacterial and anticancer efficacy.

Linklater et al. further investigated mechanical bactericidal activity using high-aspect-ratio nanostructures. Their work demonstrated that vertically aligned carbon nanotubes (VACNTs) can inactivate bacteria purely through physical deformation (Figure C). Due to their high aspect ratios and exceptional flexibility, the CNTs bend upon bacterial contact, storing elastic energy that contributes to bacterial membrane rupture. By optimizing CNT length, the authors achieved a 99.3% bactericidal rate against P. aeruginosaone of the highest reported for CNT-based surfaceshighlighting the efficacy of tailored nanomechanical forces.

Addressing the challenge of bacterial debris accumulation on static antibacterial surfaces, Jiang et al. developed a thermoresponsive hybrid system by grafting poly­(N-isopropylacrylamide) (PNIPAAm) brushes onto ZnO nanopillars. Above the lower critical solution temperature (LCST), PNIPAAm chains collapse, exposing nanopillars that achieve ∼99% mechano-bactericidal efficiency. Below the LCST, the brushes swell into a hydrophilic layer that releases >98% of killed bacteria, enabling surface renewal (Figure D). Similarly, Yi et al. fabricated a ZnO nanopillar surface grafted with zwitterionic polymer (PSBMA) brushes. Under dry conditions, the collapsed brushes permit mechano-bacterial killing; upon hydration, the swollen layer facilitates the removal of cellular debris (Figure E). Both systems ensure long-term antibacterial activity without inducing resistance, via sequential “kill-and-release” cycles governed entirely by physical mechanisms.

In addition to the inherent bactericidal capability of nanomaterials through mechanical membrane disruption, antibiotics such as colistin, lauric acid, and berberine also exert antibacterial effects by damaging bacterial membranes. However, due to their lack of targeting specificity, nanocarrier systemsincluding micelles, liposomes, dendritic polymers, and DNA nanostructuresare often employed as delivery vehicles to enhance targeting efficacy and therapeutic outcomes, thereby achieving more efficient antibacterial activity. −

In summary, the field of physical antibacterial strategies is advancing from static, single-mechanism materials toward dynamic, multimodal, and intelligent systems. Recent developmentsincluding photothermal enhancement, chemical synergy, optimized nanomechanics, and stimuli-responsive “kill-and-release” interfacesillustrate a clear trend toward integrated and resistance-free antimicrobial solutions. These sophisticated nanomaterial platforms hold significant promise for applications in biomedical devices, healthcare, and beyond.

4.1.2. Stimuli-Responsive Antimicrobial Therapies

Stimuli-responsive anti-intratumoral bacteria therapies represent an advanced precision medicine paradigm that moves beyond conventional membrane disruption mechanisms. These strategies exploit distinctive pathological cuessuch as acidity, hypoxia, or enzyme activityor external triggers including light and ultrasound to locally generate lethal hyperthermia or ROS. Key modalities include PTT, which transforms light energy into heat, as well as PDT and sonodynamic (SDT) therapies that employ light and ultrasound, respectively, to activate ROS production. −

This approach enables spatiotemporally controlled antibacterial activity with significantly minimized off-target effects and collateral damage.

Exemplifying this targeted methodology, Xin et al. developed a cascade-targeting nanoplatform (CMGH) for precise eradication of intratumoral Fn. The system features a GalNAc-modified core cloaked by an acid-responsive hyaluronic acid shield, which initially promotes tumor accumulation. Upon exposure to the acidic tumor microenvironment, the shield dissociates, exposing GalNAc ligands that specifically bind to Fap2 lectin on Fn. Subsequent near-infrared irradiation induces localized hyperthermia, directly ablating the bacteria. Notably, this targeted PTT not only eliminates Fn but also reduces immunosuppressive succinic acid levels, thereby reversing Fn-mediated immunosuppression and enhancing antitumor immunity (Figure A).

4.

Antibacterial mechanisms of nanomaterials activated by physical stimulation to generate heat or ROS. (A) Schematic of a cascade-targeting nanotherapeutic for enhanced photothermal-immunotherapy. Its “shielding-deshielding” design enables sequential targeting of colorectal tumors and intratumoral Fn, generating an NIR-II photothermal agent in situ. The reinforced PTT induces immunogenic cell death and eradicates Fn, which reduces succinic acid-mediated suppression of T-cell trafficking, thereby potentiating antitumor immunity. Reproduced with permission from ref , Copyright 2025, Elsevier. (B) Schematic illustration of d-Ala-TPApy-labeled Clostridium butyricum for malignant melanoma ablation under light irradiation. Reproduced with permission from ref , Copyright 2022, Wiley. (C) Schematic illustration of nanosonosensitizer-engineered bacteria for sonodynamic therapy. These bacteria target tumors, generate oxygen in situ via catalase to alleviate hypoxia, and produce ROS under ultrasound to kill tumor cells, enabling PA/US/FL multimodal imaging. Reproduced with permission from ref , Copyright 2024, Elsevier. (D) Scheme of Au@BSA-CuPpIX eliminating core pathogenic bacteria in CRC to boost SDT and alleviate skin photosensitivity. Reproduced with permission from ref , Copyright 2023, American Chemical Society.

Shi et al. advanced this paradigm through a biointegrated strategy combining metabolically engineered bacteria with PDT for melanoma treatment. By incorporating a d-alanine-conjugated AIE photosensitizer into Clostridium butyricum via metabolic labeling, they created a system where bacteria first colonize hypoxic tumor regions. Subsequent bacterial migration to oxygen-rich zones and lysis releases the photosensitizer in situ. Light irradiation then activates PDT, generating ROS to sequentially ablate both hypoxic and normoxic regions, achieving complete tumor and intratumoral bacteria eradication (Figure B).

Addressing the critical challenge of tumor hypoxia, Wang et al. constructed an innovative biohybrid system (CB@HPP) that synergizes catalase-expressing bacteria with nanosonosensitizers. The engineered bacteria exploit natural tumor tropism for targeted delivery and continuously decompose endogenous H₂O₂ into oxygen, alleviating hypoxia. This in situ oxygen supply significantly enhances SDT efficacy under ultrasound irradiation, promoting abundant ROS generation. Furthermore, integrated fluorescence/photoacoustic/ultrasound multimodal imaging enables real-time monitoring of tumor colonization and precise treatment guidance, demonstrating a robust theranostic platform with superior antitumor performance and biocompatibility (Figure C). Qu et al. further expanded the combinatorial frontier by developing a dual-mode nanoplatform (Au@BSA-CuPpIX) for targeting intratumoral Fn. This system concurrently employs SDT and PTT, generating ROS under ultrasound while producing photothermal effects under laser irradiation. The synergistic action not only facilitates efficient bacterial clearance but also enhances tumor cell apoptosis through downregulation of antiapoptotic proteins. A key safety advancement involves the gold nanoparticle core, which mitigates the cutaneous phototoxicity typically associated with porphyrin accumulation. This pathogen-targeting strategy thus improves primary tumor treatment and inhibits lung metastasis, offering a promising therapeutic approach with reduced side effects (Figure D).

In summary, stimuli-responsive antimicrobial therapies provide a versatile and powerful toolkit for precision intervention. By leveraging specific triggers to locally activate cytotoxic agents, these strategies effectively address limitations of conventional antibiotics, including poor specificity, antimicrobial resistance, and damage to commensal microbiota. The continued evolution of these intelligent systems is positioned to redefine the landscape of targeted anti-infective and combination therapies.

4.2. Chemical Damage Mechanisms

Chemical damage mechanisms represent a cornerstone of nanomaterial-enabled antibacterial strategies. This section delves into two principal modes of action: the release of lethal metal ions (e.g., Ag⁺, Zn^{2 +}) that disrupt critical cellular processes, and the catalytic generation of ROS to induce fatal oxidative stress in bacteria, thereby effectively eliminating intratumoral pathogens.

4.2.1. Ion Release

A primary antimicrobial mechanism of nanomaterials is through the release of ions such as Ag⁺, Zn^{2 +}, and Cu^{2 +}, through which they efficiently achieve microbial eradication. −

Capitalizing on the elevated copper demand in breast cancer, Xie et al. developed zinc-chelated Zn-PEN as a therapeutic nanoagent (Figure A). Theoretical calculations confirmed a strong chelation affinity for Cu²⁺, driving a spontaneous ion exchange process in which Zn-PEN sequesters Cu²⁺ while releasing Zn²⁺a transformation visually evidenced by a color change from silver-white to light blue (Figure B). Zn-PEN exhibited potent antibacterial activity against Fn, causing complete cellular disintegration as observed by SEM, in contrast to the limited structural disruption induced by Zn²⁺ alone. This bactericidal effect was further supported by live/dead staining, which showed predominantly red fluorescence in treated groups, indicating extensive bacterial death. Consequently, Transwell assays demonstrated that Zn-PEN effectively suppressed Fn-enhanced migration and invasion of 4T1 cells (Figure C). In vivo, Zn-PEN concurrently reversed Fn-induced immunosuppression, as evidenced by increased T-cell infiltration, inhibited tumor metastasis, illustrating its dual antibacterial and immunomodulatory functions.

5.

Antibacterial chemical mechanisms via ion release and enzyme-mimetic ROS generation. (A) Mechanism by which Zn-PEN achieves a synergistic therapy for antitumor, antibacterial, and antimetastatic effects. (B) Reaction energy diagram and schematic of Cu^{2 +} replacing Zn^{2 +} in Zn-PEN, along with corresponding images of Zn-PEN chelating Cu^{2 +}. (C) Antibacterial efficacy against Fn and its impact on cancer cells. (a) Colony formation and SEM images showing bactericidal effects. (b) Bacterial viability assessed by fluorescent staining (SYTO9 for live cells; PI for dead cells), revealing treatment-induced membrane disruption. (c) Transwell assay schematic for evaluating 4T1 cells migration and invasion postinfection. Reproduced with permission from ref , Copyright 2025, Wiley. (D) Construction of an antibacterial-augmented antitumor nanomedicine (ADEN). Ultrasmall Ag NPs grown in porous DMSNs inhibit intratumoral Fn to alleviate bacteria-induced chemoresistance, enhancing chemotherapy efficacy. Reproduced with permission from ref , Copyright 2023, Elsevier. (E) Au/Pt NCs@GOX clusterzyme for synergistic periodontal therapy. It initiates a glucose-fueled cascade reaction to generate ·OH, eradicating Fn biofilms and alleviating periodontitis. Reproduced with permission from ref , Copyright 2023, Spring Nature. (F) Synthesis and function of BSA-Cu SAN in destroying pathogen-tumor symbionts for antitumor therapy. Reproduced with permission from ref , Copyright 2023, Elsevier.

In a complementary antibacterial strategy, platforms based on Ag⁺ exert their effects by specifically binding to bacterial DNA, thereby inhibiting replication. A representative example utilizes a coordination–redox strategy to achieve the homogeneous in situ growth of ultrasmall silver nanoparticles (AgNPs) within dendritic mesoporous silica nanoparticles, which are simultaneously loaded with chemotherapeutic agents. The released Ag⁺ ions not only disrupt bacterial DNA replication but also contribute to membrane penetration and ROS generation, collectively enhancing bactericidal activity. This integrated system effectively clears Fn, suppresses bacteria-induced autophagy in colorectal cancer cells, overcomes chemoresistance, and significantly augments antitumor efficacy (Figure D). Extending this paradigm, Dong et al. developed an M13@Ag nanocomposite for precision antibacterial therapy. The system exploits the M13 phage for selective targeting of Fn, enabling localized delivery of AgNPs. The released Ag⁺ ions exert direct bactericidal effects by disrupting essential bacterial processes. This antibacterial action subsequently triggers immunomodulationreducing immunosuppressive MDSCs and activating antigen-presenting cellsthereby collectively remodeling the tumor microenvironment to improve therapeutic outcomes.

In conclusion, the integration of antibacterial functionality into nanomedicine design represents a strategic evolution in cancer treatment. By specifically targeting intratumoral bacteria such as Fusobacterium nucleatum, these stimuli-responsive systems not only eradicate pathogens but also reverse associated immunosuppressive and chemoresistant effects. This dual-action paradigm, which merges direct bactericidal activity with potentiation of host antitumor immunity, opens a promising avenue for developing refined combination therapies against cancers associated with microbial dysbiosis.

4.2.2. Reactive Oxygen Species (ROS) Generation

Chemodynamic Therapy (CDT), which employs catalytic nanomaterials to convert endogenous substrates (e.g., H₂O₂) into destructive ROS, represents a potent strategy for eradicating intratumoral bacteria. The classic Fenton reaction, a central mechanism within the broader CDT paradigm, utilizes iron species to catalyze H₂O₂ into ·OH. In this context, nanozymes have emerged as a highly promising class of materials due to their ability to mimic key enzymatic activities and efficiently generate ROS from endogenous substrates within the tumor microenvironment.

The development of nanozymesnanomaterials mimicking natural enzymeshas been central to this strategy.

This field originated from the seminal 2007 discovery of intrinsic peroxidase-like activity in ferromagnetic nanoparticles, which later led to the formal introduction of the term “nanozyme” in 2013 to describe this class of next-generation artificial enzymes with enzyme-like properties.

These functional nanomaterials, particularly metal-based ones, catalyze the generation of ROS such as ·OH, O₂ ^–, and H₂O₂ from endogenous substrates (e.g., H₂O₂), which induce bacterial death by damaging membranes, proteins, and DNA. Thus, nanozymes serve as pivotal catalytic generators of ROS, playing a key role in mediating antibacterial effects through enzymatic reactions. −

Wang et al. developed a bimetallic clusterzyme (Au/Pt NCs@GOX) for the treatment of oral biofilm-induced periodontitis. This integrated nanozyme system combines platinum-substituted gold nanoclusters with glucose oxidase (GOX) to achieve synergistic antibacterial effects. The Au/Pt nanoclusters display enhanced peroxidase-like activity, while GOX catalyzes the oxidation of glucose in the nutrient-rich oral environment. Through cascade catalysis, the system efficiently converts endogenous glucose into highly toxic hydroxyl radicals directly at the infection site, enabling effective eradication of Fn biofilms without the need for high concentrations of external H₂O₂ (Figure E). Both in vitro and in vivo experiments confirmed that this clusterzyme not only removes biofilms and alleviates inflammation but also promotes periodontal tissue regeneration, demonstrating excellent biosafety. This work establishes a novel nanozyme-based strategy for the precise and efficient treatment of oral infectious diseases via self-enhanced ROS generation.

In a separate study, Wang et al. designed a protein-supported copper single-atom nanozyme (BSA-Cu SAN) to disrupt the symbiotic relationship between intratumoral pathogens and colorectal cancer. Inspired by the structure of natural enzymes, this nanozyme concurrently generates ROS and depletes glutathione (GSH), inducing intracellular redox imbalance. Through passive tumor targeting, BSA-Cu SAN effectively eliminates Fn in situ, thereby breaking the pathogen-tumor symbiosis and overcoming Fn-mediated autophagy that confers ROS resistance (Figure F). This dual-action mechanism synergistically promotes cancer cell apoptosis while avoiding long-term systemic toxicity due to efficient renal clearance, establishing a new paradigm for targeting pathogen-tumor symbionts in anticancer therapy.

To address inherent limitations of CDTsuch as insufficient endogenous H₂O₂ and overexpression of GSHa MoS₂/CuO₂ hybrid nanozyme was developed. This system enhances CDT through a self-reinforcing mechanism: CuO₂ simultaneously supplies H₂O₂ and depletes GSH, while the MoS₂ component facilitates the reduction of Cu^{2 +} to the more catalytically active Cu⁺ via Mo^{4 +}/Mo^{6 +} redox cycling.

Mechanistically, nanomaterials eliminate tumor-associated bacteria primarily through ROS generated via nanozyme catalysis or Fenton-like reactions. This oxidative stress damages bacterial membranes, DNA, and proteins, ultimately disrupting bacterial viability. By eradicating pro-tumorigenic bacteria, ROS-mediated targeting modulates the tumor microbiome and serves as an effective adjuvant strategy to enhance antitumor efficacy.

4.3. Biological Damage Mechanisms

4.3.1. Metabolic Interference

Metabolic interference represents a sophisticated antibacterial strategy that moves beyond broad-spectrum mechanisms to target specific physiological processes essential for bacterial survival. This approach encompasses the direct disruption of energy metabolism and enzymatic functions by catalytic nanomaterials, as well as the intelligent, targeted delivery of conventional antibiotics. By exploiting bacterial metabolic vulnerabilities within the tumor niche, these interventions aim to precisely neutralize intratumoral pathogens while minimizing off-target effects, thereby overcoming their pro-tumorigenic activities, including therapy resistance.

Emerging evidence indicates that intratumoral bacteria can promote resistance to gemcitabine chemotherapy. This phenomenon is largely attributed to CDD expressed by bacteria within tumors, which metabolizes gemcitabine into its inactive form. Nitrogen-doped carbon nanospheres (N-CSs) have been employed as dual-function nanomaterials: they act as CDD nanoinhibitors to counteract bacteria-mediated gemcitabine resistance and as nanoenzymes to integrate catalytic therapy with chemotherapy (Figure A). Mechanistic studies demonstrate that N-CSs competitively inhibit CDD activity through comparable contributions from short-range Lennard-Jones and Coulombic interactions, effectively mitigating drug resistance (Figure B,C). Notably, non-N-doped CSs maintained CDD inhibitory activity, whereas PEG-modified N-CSs lost efficacy (Figure D,E), highlighting the critical role of hydrophobic interactions. Both experimental and simulation data confirmed that N-CSs bind more strongly than gemcitabine to bacterial CDD via polar oxygen groups and hydrophobic graphene domains. Beyond CDD inhibition, N-CSs exhibit peroxidase-like catalytic activity (Figure F) and deplete intracellular GSH (Figure G), achieving multitarget suppression of drug-resistant tumors. In vitro studies further validated that N-CSs can reverse gemcitabine resistance induced by intratumoral bacteria (Figure H).

6.

Antibacterial action via bacterial metabolic interference. (A) Schematic of N-CS-induced inhibitory effects against CDD expressed by bacteria to metabolize Gem into dFdU. (B) CDD active pocket, geometric structures (uridine/Gem/CM-1-3), and MD-simulated binding conformations with key H-bond residues. (C) Interaction energies between CDD and four ligands, including short-range Coulombic interaction energy (E _Coul), short-range Lennard-Jones energy (E _L‑J), and their summaries E _Int in kJ mol^–1. (D, E) Concentration changes of Gem and dFdU in the presence of PEG-N-CSs and CSs, respectively. (F) UV–vis absorbance spectra and color changes of TMB in different reaction systems: (1) TMB, (2) TMB + H₂O₂, and (3) TMB + H₂O₂+ N-CSs in a HAc-NaAc buffer (pH 4.5) after 3 min of incubation at 37 °C. (G) Reduction of GSH treated with the N-CSs and H₂O₂ (1 mM). (H) Cell viability after culture with Gem, Gem/E. coli, and Gem/E. coli/N-CSs for 24 h. Reproduced with permission from ref , Copyright 2022, Elsevier. All data were analyzed in GraphPad Prism 7. The significance of the data was analyzed according to unpaired Student’s two-sided t test: *p < 0.05, * *p < 0.01, * **p < 0.001. (I) Scheme illustration of the antibacterial mechanism of MTZ/Ftn-DOX@HM. Reproduced with permission from ref , Copyright 2024, American Chemical Society. (J) Scheme illustration of the antibacterial mechanism of metronidazole–fluorouridine nanoparticles (MTI-FDU). Reproduced with permission from ref , Copyright 2023, American Chemical Society.

Complementing this approach, Kong et al. implemented a metabolism-engineered phototherapy strategy using an Nb₂C/Au nanocomposite. This system synergizes physical photothermal ablation with chemical disruption of bacterial metabolic pathways, as validated by metabolomics. This dual interference alters microbial abundance and diversity, effectively undermining bacterial survival and pro-tumorigenic functions.

Antibiotics remain a cornerstone for inhibiting bacterial metabolism and achieving antibacterial effects. − However, their broad-spectrum nature often induces systemic toxicity due to a lack of specificity. Targeting intratumoral bacteria poses unique challenges distinct from conventional infections, including considerations of material size, safety, and the complex tumor microenvironment. Leveraging nanotechnology, researchers have developed innovative nanocarriers for targeted antibiotic delivery within tumors. −

To achieve precise intratumoral antibiotic delivery without disrupting the systemic microbiota balance, Geng et al. engineered a sophisticated biomimetic nanovehicle by fusing membranes from Fn and red blood cells. This unique hybrid coating grants the nanovehicle both long circulation and specific tumor-homing capabilities. Loaded with metronidazole, it facilitates the targeted depletion of intratumoral Fn, thereby alleviating its suppression on the host immune system and potently synergizing with PD-L1 blockade therapy, offering a safe and effective strategy to combat bacterially associated immunotherapy resistance (Figure I). Further refining selectivity, Gao et al. constructed metronidazole-fluoropyridine nanoparticles (MTI-FDU) that release antibiotics upon GSH-triggered disassembly in the tumor microenvironment. This design targets tumor-associated bacteria while sparing the gut microbiota, with concurrent release of fluorouridine to kill cancer cells in hypoxic regions (Figure J).

The pursuit of precision continues with a nano-Mupirocin platform that selectively targets intratumoral Fn without disrupting intestinal flora. Mupirocin inhibits bacterial protein synthesis by reversibly binding to isoleucyl-tRNA synthetase. In AT3 mouse models, the nanoliposome successfully targeted intratumoral bacteria. Combinatorial strategies are crucial to overcome bacterial-induced chemoresistance. Xiaodong Zhang et al. developed self-traceable nanoreservoirs coloaded with gemcitabine and ciprofloxacin, decorated with hyaluronic acid for tumor-targeted delivery.

These nanoreservoirs effectively eradicate intratumoral bacteria and inhibit tumor growth, ciprofloxacin inhibiting bacterial DNA synthesis by targeting DNA gyrase, an essential replication enzyme. A related approach integrates the photosensitizer CyI and doxycycline into thermosensitive tumor-derived exosome fusion liposomes (ECDL), enable homologous tumor targeting and localized antibiotic release to eliminate tumor-associated bacteria. These advancements highlight the potential of nanotechnology to overcome challenges in tumor-associated bacterial management while minimizing systemic toxicity and preserving gut microbiota balance.

Collectively, the strategic application of nanomaterials for metabolic interference establishes a sophisticated paradigm for controlling tumor-associated bacteria. These approaches effectively disrupt fundamental bacterial processesspanning energy metabolism, enzymatic function, and macromolecular synthesisthrough mechanisms that include ion-mediated inhibition, nanozyme catalysis, and spatially controlled antibiotic delivery. By precisely targeting bacterial survival machinery and countering their role in chemoresistance, such metabolic interventions significantly potentiate antitumor efficacy while preserving microbial homeostasis, paving the way for more selective and effective cancer therapeutics.

4.3.2. Biofilm Inhibition

Bacterial biofilms are protective structures that significantly enhance microbial resistance to antimicrobial agents. Notably, specific pathogens such as enterotoxigenic Bacteroides fragilis, Clostridioides difficile, and Fn have been demonstrated to promote cancer progression through biofilm formation. These pathogens employ various mechanisms to drive tumorigenesis.

Consequently, suppressing these pathogenic biofilms presents a compelling antibacterial strategy. Nanomaterials have emerged as potent tools for biofilm suppression, capable of either preventing their formation or disrupting established colonies. They physically compromise the biofilm architecture and inhibit the bacterial adhesion and aggregation that underpin biofilm development. For instance, Gao and colleagues constructed a supramolecular nanomedicine, PG-Pt-LA/CB[7], whose antibacterial mechanism is primarily mediated by the release of lauric acid (LA). LA serves as the key antibacterial agent, directly eradicating Fn and leading to a significant reduction in its abundance within the tumor. Furthermore, the treatment profoundly alleviates the associated inflammatory response by substantially suppressing the NF-κB signaling pathway and downregulating the expression of pro-inflammatory cytokines, including TNF-α and IL-6. This combined action of direct bacterial clearance and inflammation reduction effectively counteracts the microbe-induced chemotherapy resistance.

Furthermore, metal-based nanomaterials effectively suppress Fn and its biofilms through multifaceted antibacterial mechanisms. Their high surface area and small size enable them to primarily disrupt bacterial cell membrane integrity. For instance, polycationic silver nanoclusters exhibit potent and sustained antibacterial activity with minimal resistance development by effectively targeting and penetrating the bacterial membrane. The release of metal ions is another critical antibacterial mechanism. Zinc-based ZIF-8 nanoparticles release Zn^{2 +} ions that contribute to antibiofilm efficacy, while the shape-dependent activity of nano-CeO₂, particularly octahedral structures with higher Ce^{3 +} content, inactivates bacterial surface proteins through interaction with thiol groups.

In summary, the strategic application of nanotechnology represents a transformative approach to targeting tumor-promoting bacterial biofilms. By leveraging bacteria-responsive mechanisms and the intrinsic antimicrobial properties of nanomaterials, these innovative systems not only disrupt biofilm integrity but also reverse associated chemoresistance. As research advances, nanomaterial-based therapies hold significant potential to enhance cancer treatment outcomes by addressing the critical interplay between pathogenic biofilms and tumorigenesis.

4.3.3. Immune Modulation

Nanomaterials serve as potent immunomodulatory platforms that either intrinsically activate immune responses or precisely deliver immunostimulatory agents to target tumor-associated bacteria. This approach effectively harnesses the host immune system to eliminate intratumoral pathogens while generating synergistic antitumor effects, representing a promising strategy for combinational cancer therapy.

These nanomaterials enhance immune function through multiple mechanisms. Certain types can activate macrophages, augmenting their phagocytic and bactericidal capabilities, while others function as immune adjuvants to potentiate the host’s antibacterial immune responses. A notable example is a photothermal system that integrates gold nanoparticles (AuNPs) onto Nb₂C nanosheets with anti-TNFα, demonstrating enhanced immunomodulatory activity. The chelation of Au in this system significantly reduced the IC_{5 0} values, lowering the required power density from 1.166 to 1.096 W cm^–2 and the Nb concentration from 94.07 to 56.48 μg mL^–1.

The strategic design of nanoplatforms has enabled multiple immunomodulatory pathways. Researchers have developed an ellagic acid-endogenous protein nanocomposite that leverages the enhanced permeability and retention (EPR) effect for tumor targeting. This composite effectively reduces intratumoral bacterial load and modulates antitumor immunity. The underlying mechanism involves a decrease in microbial abundance and diversity, which leads to metabolic alterations in the tumor microenvironment. It is hypothesized that eP-EA enhances cancer immunotherapy by targeting bacteria and potentially reducing their production of histamine, a molecule implicated in microbe-promoted tumor progression.

Further advancing this frontier, biologically interfaced extracellular vesicles (BEVs) wrapped with responsive nanocloaks have been engineered to enhance immune reactivity. These stealth BEVs (cBEVs) not only circumvent systemic side effects but also promote dendritic cell maturation via activation of the cGAS-STING pathway, demonstrating efficacy against both intratumoral bacteria and breast tumors.

As a preventive nanovaccine, cBEV confers robust protection against bacterial infection and tumor challenges. Nanovaccine technology has also seen significant progress.

A multivalent bacterial vaccine utilizing PLGA nanoparticles codelivers a broad-spectrum of antigens and adjuvants, eliciting potent pathogen-specific immunity while preserving commensal microbiota (Figure A). The antigen preparation process was optimized using urea-based lysis, which yielded higher protein concentrations and more comprehensive antigen profiles compared to traditional PBS extraction, as confirmed by BCA assay and SDS-PAGE analysis (Figure B). Subsequent in vitrostudies demonstrated that these PLGA/Ags complexes potently activate dendritic cells, priming downstream immune responses (Figure C), and establish durable protective immune memory (Figure D). The versatility of such nanovaccine approaches is further corroborated by related studies in the field (Figure E).

7.

Antibacterial mechanisms through immunomodulation. (A) Schematic illustrates that the antibacterial immune response induced by PLGA/Ags vaccine effectively prevents bacteria-induced tumor metastasis. (B) Protein concentration of lysates obtained from Fn, S. sanguis, E. faecalis, and S. xylosus after sonication in urea and PBS solutions. US, Ultrasonic lysis; SDS–PAGE analysis of proteins from markers, and ultrasonic lysates of Fn, S. sanguis, E. faecalis and S. xylosus in urea and PBS solutions. (C) Flow cytometric analysis of BMDC maturation and secreted cytokine levels (IL-12p70, TNF-α, IL-6) across treatment groups (mean ± SD, n = 3). (D) Flow cytometry analysis and quantification of effector memory T cells (T_EM, CD44⁺CD62L^–) and central memory T cells (T_CM, CD44⁺CD62L⁺) within CD8⁺ T cells, along with CD19⁺CD38^– memory B cells within CD45⁺ lymphocytes, in mice with or without PLGA/Ags vaccine treatment. All data are presented as means ± SD (n = 3). Reproduced with permission from ref , Copyright 2025, AAAS. (E) Schematic illustrating the preparation of LipoFM-CPG. Reproduced with permission from ref , Copyright 2024, Elsevier. (F) Schematic illustration of phage-based bio/abiotic hybrid system (M13@Ag) to regulate gut microbes for cancer-specific immune therapy. Reproduced with permission from ref , Copyright 2020, AAAS.

Complementing these strategies, Dong et al. developed an M13@Ag nanocomplex that synergizes bacteriophage precision with the bactericidal activity of silver nanoparticles. The system specifically binds to intratumoral Fn via the M13 phage, leading to direct bacterial clearance by the surface-loaded AgNPs. Concurrently, the phage component remodels the immunosuppressive microenvironment by activating antigen-presenting cells and reducing myeloid-derived suppressor cells. When combined with PD-1 inhibitors or chemotherapy, this immunotherapeutic approach significantly prolongs survival in murine models of colorectal cancer (Figure F).

Collectively, these advancements underscore the paradigm of using nanomaterials to modulate immune responses for enhanced antimicrobial and antitumor defense. By enabling targeted delivery and precise activation of immune pathways, nanomaterial-based strategies effectively disrupt the pathogen-tumor symbiosis, inhibit metastasis, and amplify therapeutic efficacy, offering a powerful dual-action modality for modern cancer therapy.

4.4. Synergistic Antimicrobial Mechanisms

In practical applications, the antimicrobial effects of nanomaterials often arise from the synergistic interplay of multiple mechanisms. For instance, certain nanomaterials not only release iron to disrupt bacterial cell membranes but also catalyze the production of ROS in the presence of substrates and inhibit biofilm formation. This multimechanism synergy enhances the efficiency and broad-spectrum efficacy of nanomaterials as antimicrobial agents.

ZnO NPs, which exhibit both antitumor and antibacterial effects, exemplify this synergistic approach. Their bactericidal activity involves multiple mechanisms, including ROS-mediated disruption of bacterial cell membranes and the release of Zn²⁺ ions, which bind to bacterial cell membrane proteins and nucleic acids, disrupting normal cellular functions. ZnO NPs have demonstrated promising applications in antitumor bacteriology research. Given the negative charge of both Gram-negative and Gram-positive bacterial cell membranes, ZnO NPs first cause mechanical damage by disrupting membrane integrity before entering the bacterial cells. , A similar multiantimicrobial mechanism has been reported in other studies on ZnO NPs with synergistic antimicrobial activity. Huang et al. developed gallium-based metal–organic framework (MOF) nanoparticles as delivery vehicles to enhance the ability of gentamicin to eradicate intracellular bacteria. These gallium-containing carriers also impair microbial activity by interfering with iron metabolism, thereby increasing bacterial susceptibility to antibiotics. Furthermore, gallium ions exhibit inherent antibacterial activity, and their synergistic interaction with antibiotics significantly enhances the bactericidal effect. In conclusion, MOF-based drug delivery strategies may offer innovative solutions for extending the efficacy of existing antibiotics, thereby prolonging their clinical utility.

Nanoplatforms combat tumor-linked bacteria through three key mechanisms, enhancing cancer treatment. Physically, nanomaterials destroy bacterial membranes using sharp edges, heat, or ROS. Chemically, released ions (e.g., Ag⁺, Zn^{2 +}) damage bacterial components, while ROS and metabolic disruption weaken their survival. Biologically, they boost antitumor immunity by activating immune cells or using nanovaccines. Combined approaches like ZnO NPs (ion release + ROS) or nanovaccines (antigen delivery + immune activation)-overcome drug resistance and break the bacteria-tumor alliance more precisely. These strategies highlight nanomaterials’ potential to simultaneously target microbes and tumors, offering safer, more effective cancer therapies.

5. Conclusions and Perspectives

5.1. Conclusions

The antimicrobial mechanisms of nanomaterials encompass complex, synergistic interactions of physical, chemical, and biological pathways that disrupt bacterial integrity and functions. Future research should focus on elucidating mechanistic details, optimizing antimicrobial efficacy, and developing novel multifunctional platforms. Nanotechnology-based strategies demonstrate significant preclinical promise, providing innovative therapeutic platforms against intratumoral pathogens. The discovery of intratumoral bacteria represents a paradigm shift in oncology, establishing tumor-microbe symbiosis as a therapeutic target. Collectively, advances in antibacterial nanotechnology provide a robust foundation for targeting tumor-associated microbiota, with substantial potential for adaptation into antitumor applications. These technologies offer transformative approaches for overcoming cancer through targeted microbial modulation.

5.2. Perspectives

Nanotechnology offers a comprehensive suite of functional strategies for targeting intratumoral bacteria, encompassing precision delivery of antibacterial agents, photothermal therapy, photodynamic therapy, and immunotherapy potentiation. These approaches have demonstrated compelling preclinical efficacy. However, fully realizing nanotechnology’s potential in combating intratumoral bacteria necessitates addressing persistent challenges through dedicated research to refine these sophisticated platforms.

Despite significant advances in nanotechnology-mediated antibacterial therapies, several critical limitations remain unresolved. Foremost among these is the imperative for comprehensive assessment of nanomaterials’ long-term biosafety and toxicity profiles, particularly concerning potential adverse effects from systemic accumulation. Concurrently, developing more efficient and tumor-specific targeting methodologies is essential to optimize nanomaterial delivery to intratumoral bacterial niches. Future investigations should prioritize integrating nanotechnology with conventional anticancer modalities to achieve synergistic therapeutic outcomes.

The translation of these innovative platforms from laboratory settings to clinical practice presents substantial hurdles. Overcoming this translational gap necessitates close interdisciplinary collaboration among materials scientists, cancer biologists, infectious disease specialists, and clinical oncologists. Such concerted efforts will bridge fundamental research with therapeutic implementation. By systematically addressing these challenges through multidisciplinary partnerships, nanotechnology holds transformative potential to revolutionize the management of intratumoral bacteria and fundamentally advance cancer treatment paradigms.

The manuscript was written through the contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Published as part of ACS Applied Materials & Interfaces special issue “Nanozymes: Design, Mechanisms, and Applications”.