Photothermal therapy (PTT) and photodynamic therapy (PDT) are two major modalities of light-activated cancer treatment, each with distinct advantages and limitations. However, a concise and position-specific structural handle for modulating reactive oxygen species (ROS)-related and photothermal outputs within a single heptamethine cyanine scaffold remains lacking. Herein, we report two meso-substituted heptamethine cyanine derivatives, 038 and 048, derived from the second near-infrared (NIR-II) meso-chloro precursor 055, featuring 4-piperidineethanol and pyrrolidine substituents, respectively. These structurally similar compounds exhibited divergent phototherapeutic behaviors. Systematic photophysical studies revealed that meso-amine substitution alters absorption profiles, tunes calculated electronic structures, and differentially enhances ROS-related responses while attenuating photothermal heating. Across the series, 055 retains the strongest photothermal performance, whereas 048 exhibits the strongest ROS-related activity. Notably, under their respective in vivo irradiation conditions (808 nm for 038 and 680 nm for 048), 038 afforded better antitumor outcomes than 048, despite the stronger in vitro ROS-related response of 048. This comparison shows that a stronger in vitro ROS-related response alone did not predict a better in vivo therapeutic effect under the tested conditions. This work highlights meso-cyclic amine substitution as a concise structural handle for modulating ROS-related and photothermal outputs within a heptamethine cyanine scaffold.

OBJECTIVES:Periodontitis is an inflammatory disease driven by dysbiotic dental plaque and is the leading cause of tooth loss in adults. We aimed to develop a reactive oxygen species (ROS)-responsive drug delivery system based on polydopamine (PDA)-functionalized bovine serum albumin (BSA) nanoparticles (NPs) for the controlled release of minocycline hydrochloride (MH) and to evaluate its synergistic antibacterial and antioxidant effects. METHODS:MH-loaded BSA NPs were prepared using a desolventization method followed by PDA coating. The resulting PDA@BSA NPs@MH were characterized in terms of size, morphology, drug loading, and release kinetics. Antibacterial activity against Porphyromonas gingivalis, Streptococcus gordonii, and Fusobacterium nucleatum was assessed using live/dead staining, colony counting, and biofilm assays. ROS-scavenging activity was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and intracellular ROS assays. Biocompatibility was assessed via cytotoxicity, migration, and hemolysis tests. RESULTS:PDA@BSA NPs@MH exhibited a uniform spherical morphology (180-200 nm) with 5.68% drug loading. The PDA coating enabled sustained MH release and concentration-dependent DPPH scavenging. The nanoparticles demonstrated potent antibacterial activity (mortality > 77% at high concentrations) and biofilm inhibition (>96%). Intracellular ROS levels were significantly reduced in LPS-stimulated macrophages. Furthermore, no evident cytotoxicity was observed, cell migration was enhanced, and hemolysis rates were <5%. CONCLUSIONS:The PDA@BSA NPs@MH platform integrates MH-mediated antibacterial activity with PDA-mediated antioxidant activity, effectively addressing both bacterial infection and oxidative stress in periodontitis.

Ferrocene derivatives possess a typical "sandwich" structure that facilitates the formation of two-dimensional nanosheets (2D NSs), while their ferrous ions can effectively mediate chemodynamic therapy (CDT). However, conventional bottom-up synthesis methods for nanosheets often involve complex processes and stringent preparation conditions, limiting their therapeutic applications. In this study, we developed a simple yet efficient premix-dropwise-stir synthetic strategy to fabricate ultrathin oleanolic acid/perfluorocarbon-ferrocene (O/F-Fc) 2D NSs with considerable antitumor properties. The incorporation of oleanolic acid (OA) effectively inhibited F-Fc self-aggregation and facilitated the formation of ultrathin nanosheets (∼1.5 nm), while simultaneously enhancing the CDT efficacy of F-Fc through synergistic effects. Comprehensive in vitro and in vivo studies demonstrated that these carrier-free 2D NSs possess multifunctional capabilities, including oxygen self-supply to alleviate tumor hypoxia, generation of multiple reactive oxygen/nitrogen species to amplify oxidative stress and enhance CDT, antifibrotic activity, promotion of macrophage M1 polarization to activate immune responses, and enhanced deep tumor penetration, collectively enabling effective tumor microenvironment (TME) remodeling. This study not only presents an approach for preparing ultrathin ferrocene-based carrier-free 2D NSs, but also offers mechanistic insights into developing carrier-free organic 2D nanosystems for synergistic TME remodeling and enhanced CDT efficacy in cancer therapy.

The clinical management of hypertrophic scars (HSs) remains challenging due to their complex etiology and heterogeneous morphology, underscoring the need for multitarget treatment strategies. In this study, we developed a nanocomposite system constructed through the metal–phenolic network–mediated self-assembly of molybdenum polyoxometalate (Mo154) and epigallocatechin gallate (EGCG), followed by chitosan encapsulation, to generate chitosan-encapsulated Mo154/EGCG (CME) nanoparticles. These nanoparticles were integrated into dissolvable microneedles (CME@MN) to enable transdermal administration. Under near-infrared laser irradiation, CME exhibited a three-pronged therapeutic effect: suppression of collagen overproduction and excessive extracellular matrix (ECM) deposition in human keloid fibroblasts, regulation of proliferation and migration in human umbilical vein endothelial cells, and reprogramming of macrophages toward a proinflammatory M1 phenotype. In vivo, CME@MN patches preferentially accumulated within scar tissue, where they normalized ECM organization, improved collagen fiber rearrangement, and attenuated fibroblast activity through photothermal-enhanced mechanisms while maintaining an excellent safety profile. The CME@MN system represents a potentially transformative approach to HS management by offering a unified platform that simultaneously targets the fibrotic, angiogenic, and inflammatory components of scar pathogenesis.

The rising threat of antibiotic resistance severely compromises the treatment of bacterial pneumonia, underscoring the urgent need for innovative and comprehensive therapeutic strategies. Here, we developed an innovative theranostic nanoplatform (Dex/BTGd) through the coordinated assembly of tetracycline, gadolinium ion (Gd3+) and baicalin, which acts synergistically to combat infection, enable non-invasive magnetic resonance imaging (MRI), and regulate the lung microenvironment. Dex/BTGd demonstrated potent antibacterial activity against clinically relevant pathogens, effectively disrupting biofilms and overcoming tetracycline resistance. The incorporated Gd3+ allowed targeted visualization of pulmonary infection sites by MRI, facilitating timely disease assessment. Beyond its direct antibacterial effects, the nanoplatform modulated the inflammatory microenvironment by scavenging reactive oxygen species, promoting macrophage polarization from the pro-inflammatory to the anti-inflammatory phenotype, and suppressing profibrotic transforming growth factor-β signaling. In a murine model of tetracycline-resistant Pseudomonas aeruginosa pneumonia, Dex/BTGd significantly reduced bacterial load, alleviated pulmonary edema and fibrosis, and enabled targeted MRI visualization of infected lesions. This integrated strategy of pathogen clearance, microenvironment modulation, and tissue repair offers a multifaceted solution to drug-resistant bacterial pneumonia, providing a promising blueprint for next-generation anti-infective systems.

Croconic acid (CA) dyes have attracted significant attention for antitumor therapy due to their outstanding photothermal performance. However, their further development has been limited by unclear structurephotothermal relationships and relatively low photothermal conversion efficiency (PCE). In this study, we systematically modified the indole benzene ring of CA dyes with divers electron-donating/withdrawing substituents. Through integrated UV-vis spectroscopy, PCE measurements, density functional theory (DFT) calculations, and in vitro antitumor screening, we elucidated structure-photothermal correlations and identified the optimal photothermal molecule for in vivo validation. Our findings reveal that electron-donating substituents and elevated HOMO-LUMO energy levels significantly enhance photothermal performance. The optimal CA dye (6-OMe) exhibited a 1.9-fold greater temperature increase, 1.5-fold improvement in PCE, and 12-fold increased cytotoxicity against 4T1 tumor cells in vitro compared to 4-H. Furthermore, when administered at half the dosage, 6-OMe exhibited significantly enhanced in vivo antitumor efficacy compared to 4-NO2.

BACKGROUND:Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) is frequently driven by point mutations such as EGFR T790M. This poses a major clinical challenge that significantly compromises treatment efficacy and patient survival. Conventional detection methods often rely on single-mode signaling and lack built-in validation, which limits their reliability and accessibility, particularly in resource-limited settings. METHODS AND RESULTS:We developed a tri-modal biosensor that integrates alkynyl-modified gold nanoparticles (Alk-GNP) with a molecular beacon (MB) for the multiplexed detection of EGFR T790M. The optimized system simultaneously responds to the target mutation through three distinct modes: photothermal response, colorimetric shift, and fluorescence emission, achieving detection limits of 16.81 nM, 2.41 nM, and 0.80 nM, respectively. The fluorescence modality served as the primary detection mode due to its high sensitivity, while photothermal and colorimetric signals provided real-time cross-validation to enhance overall reliability. Furthermore, the smartphone-compatible photothermal and colorimetric outputs enable portable and point-of-care data analysis, an essential feature of next-generation biosensing platforms. CONCLUSIONS:This work presents a diagnostic tool that integrates tri-modal signal outputs with built-in cross-validation, which may have implications for guiding treatment decisions in NSCLC.

Photothermal therapy (PTT) and photodynamic therapy (PDT) represent promising strategies for tumor treatment, as their synergistic effects significantly enhance cancer therapeutic efficacy. In this study, we synthesized compound 111 with second near-infrared region (NIR-II) absorption using terminal branch twisting strategy. Compared to the lead compound 55, 111 exhibits greater distortion with the dihedral angle between the two planes containing the side chains increasing from 31.9 degrees to 48.3 degrees. This structural difference facilitated intersystem crossing, thereby enhancing both photothermal conversion efficiency and singlet oxygen production. Furthermore, the introduction of polyethylene glycol (PEG) branches improves the water solubility and biocompatibility, expanding its potential for in vivo applications. Compared to lead compound, 111 exhibited excellent tumor ablation in vitro and in vivo models. This work provides an important theoretical and practical basis for the development of a new generation of synergistic therapeutic platforms in the NIR-II region.

Copper-based nanotherapeutics have emerged as a promising anticancer platform by simultaneously inducing cuproptosis and enabling multimodal therapy. However, their clinical application remains constrained by uncontrolled copper ion release, a complex tumor microenvironment (TME), and insufficient therapeutic penetration. To address these challenges, we developed a multifunctional nanoplatform (BCB) through the integration of baicalein-copper coordinated nanoparticles with a boron-dipyrromethene-derived photosensitizer. BCB exhibited a uniform spherical morphology with an average size of approximately 150 nm, excellent stability, TME-responsive release, and multiple catalytic functions, including peroxidase-like and photodynamic activities. Through synergistic chemodynamic and phototherapeutic actions, BCB effectively depleted glutathione, generated abundant reactive oxygen species, disrupted mitochondrial membrane potential, and triggered cuproptosis. In murine melanoma models, BCB plus light irradiation achieved a 75% cure rate, even at low doses. Moreover, BCB exhibited antimigratory properties and bone-penetrating capability, with selective accumulation in intramedullary tumor sites, highlighting its potential for treating bone-metastatic cancers. This multimodal nanoplatform represents a promising synergistic strategy for overcoming current therapeutic limitations in both primary and metastatic tumors.

Modulating the immunosuppressive tumor immune microenvironment (TIME) is considered a promising strategy for cancer treatment. However, effectively modulating the immunosuppressive TIME within hypoxic zones remains a significant challenge. In this work, we developed a hypoxia-responsive amphiphilic drug carrier using boron-dipyrromethene (BODIPY) dye-modified chitosan (CsB), and then fabricated a hypoxia-targeted nanotheranostic system, named CsBPNs, through self-assembly of CsB and pexidartinib (5-((5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl), PLX3397), an immunotherapeutic drug targeting tumor-associated macrophages (TAMs), for synergistic photothermal/immunotherapy and hypoxia imaging. CsBPNs demonstrated uniform size, good stability, and hypoxia-switchable fluorescence and photothermal effects, enabling deep penetration and hypoxia imaging capacities in three-dimensional tumor cell spheres and tumor tissues. In vitro and in vivo experiments showed that CsBPNs under laser irradiation promoted TAMs repolarization, reversed the immunosuppressive TIME, and enhanced the therapeutic outcome of PLX3397 in solid tumors by facilitating deep delivery into hypoxic regions and synergistic photothermal therapy. This work provides a new strategy for detecting and modulating the immunosuppressive TIME in hypoxic zones, potentially enabling more precise and effective photo-immunotherapy in the future.

Chronic liver disease ranks as the 11th leading cause of death worldwide, while hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality, representing a substantial risk to public health. Over the past few decades, the global landscape of chronic liver diseases, including hepatitis, metabolic dysfunction-associated steatotic liver disease (MASLD), liver fibrosis, and HCC, has undergone substantial changes. Copper, a vital trace element for human health, is predominantly regulated by the liver. Both copper deficiency and excess can lead to cellular damage and liver dysfunction. Copper deposition is a genetic process of copper-dependent cell death associated with mitochondrial respiration, which is associated with cardiovascular disease and IBD. However, the roles of copper overload and cuproptosis in liver disease remain largely underexplored. This article examines recent studies on copper metabolism and cuproptosis in chronic liver disease, investigating the potential of targeting copper ions as a therapeutic approach. The objective is to offer insights and guidance for future investigations in this developing field of study.

The physical and chemical properties of gold nanoparticles can significantly influence their anti-tumor efficacy. Streamlining synthesis methods to modulate these properties and enhance therapeutic effects could facilitate their translation into clinical applications. This study presents a new approach to synthesize small alkynyl-modified gold nanoparticles (Alk-GNP) at room temperature using sodium citrate and propiolic acid (PA) to reduce chloroauric acid. The resulting Alk-GNP, approximately 11 nm in size with narrow dispersion, contrasts with larger gold nanoparticles (GNP) synthesized by the classical Turkevich method using boiling water. Subsequently, a round composite (CHAM) was developed using chitosan and hyaluronic acid to co-deliver Alk-GNP and the photosensitizer methylene blue for synergistic treatment. CHAM showed excellent stability and strong CD44-positive tumor targeting capabilities. It significantly boosted photothermal activity and reactive oxygen species generation compared to current GNP-based formulations. In tumor-bearing mouse models, CHAM effectively localized in tumor tissue and exhibited potent photothermal and photodynamic therapeutic effects to inhibit tumor growth while ensuring safety. The robust data presented in this study supports the potential translation of this approach, offering a simplified preparation process and improved tumor treatment efficacy.

The challenging treatment outcomes for nonsmall cell lung cancer (NSCLC) necessitate the development of innovative therapeutic strategies. In this work, we developed a multifunctional nanoplatform by modifying mesoporous silica nanoparticles (MSNs) with an aptamer (Apt) targeting epidermal growth factor (EFGR), and coloading a sonosensitizer, hematoporphyrin (HP), along with the natural nitric oxide (NO) donor, l-arginine (l-Arg). The resulting Apt-modified MSN loaded with l-Arg and HP (designated as AMLH) was designed for the targeted gas-assisted sonodynamic therapy (SDT) of NSCLC. AMLH exhibited an appropriate particle size, good drug loading ability, and ultrasound-responsive drug release. The coloading of HP and l-Arg resulted in higher encapsulation efficiency compared to single-drug loading, and AMLH remained stable when stored at 4 degrees C for 15 days. AMLH was capable of generating reactive oxygen species (ROS) and NO under ultrasound stimulation, leading to the further production of peroxynitrite (ONOO-). AMLH demonstrated specific targeting and recognition of EGFR-positive NSCLC cells, with preincubation of free Apt reducing cellular uptake, confirming the specificity of the Apt-functionalized nanoparticles. Cellular distribution studies revealed that AMLH was primarily localized in lysosomes after internalization. MTT assays and live/dead cell staining confirmed the superior cytotoxicity of AMLH, which effectively inhibits cell proliferation through mitochondrial membrane potential collapse and nuclear damage under ultrasound stimulation. These results highlight the combined efficacy of EGFR targeting, SDT, and NO gas therapy, offering a promising strategy to improve the NSCLC treatment outcomes.

Photothermal therapy (PTT) is a promising noninvasive cancer treatment with high spatial-temporal selectivity and low systemic toxicity. However, its efficiency is restricted by the poor photostability, low tumor selectivity and inadequate deep tumor penetration of current photothermal agents. This study synthesized oleanolic acid (OA)-modified chitosan (CsO) using click chemistry and developed a nano-photothermal agent (COI) through the self-assembly of CsO and a representative photothermal agent indocyanine green (ICG). COI possessed a particle size of approximately 120 nm, good physical stability, and pH-responsive drug release properties. Under 808 nm laser irradiation, COI exhibited high photothermal conversion efficiency and photostability. The cellular uptake of COI in B16 and 4T1 cancer cells was several-fold higher than that of free ICG, while remaining comparable to ICG in normal 3T3 cells. CsO inhibited cancer-associated fibroblasts proliferation and modulated the tumor microenvironment by reducing alpha-smooth muscle actin expression, enhancing deep penetration of COI in threedimensional multicellular tumor spheres and solid tumors. The promising anti-proliferative effects of COI in vitro and in vivo indicated notable synergistic effects between the chemotherapeutic effect of OA and the photothermal therapeutic effect of ICG. These results suggest that COI could serve as a promising deep tumor-penetrating nanophotothermal agent for enhanced chemo-photothermal anticancer therapy.

Breast cancer is characterized by notable heterogeneity and remains one of the leading causes of cancer‑related death among women. Autophagy, a process by which cells use lysosomes to degrade cytoplasmic proteins and damaged organelles, is not only associated with chemotherapy resistance, but is also involved in immune‑mediated tumor cell killing and immune evasion, making it a promising target for cancer therapy. Pharmacological inhibition of autophagy in breast cancer cells suppresses tumor progression. In the present study, the small molecular compound FZU‑0045‑053 (053) was identified, which exhibited autophagic and immunomodulatory effects. The effect of 053 on autophagy regulation in breast cancer cells was evaluated using transmission electron microscopy, an mRFP‑GFP‑ microtubule‑associated protein 1 light chain 3 (LC3) tandem fluorescent adenovirus, the CYTO‑ID Autophagy Detection Kit and western blot analysis. Cell viability was subsequently assessed with proliferation assay and ATP assay kits. Apoptosis induction and the expression of immune‑related molecules were measured by flow cytometry. Furthermore, a triple‑negative breast cancer mouse model was established to validate the antitumor and autophagy‑modulating effects of 053 in vivo using immunofluorescence and immunohistochemical staining. Finally, a 4T1 syngeneic mouse model was utilized to corroborate the immunomodulatory effects of 053 in vivo through immunohistochemistry and flow cytometric analysis. The findings indicated that 053 regulated autophagy in the breast cancer cell lines MDA‑MB‑231 and MCF‑7, similar to the late autophagy inhibitor chloroquine. This regulation resulted in the accumulation of autophagic substrates, specifically LC3‑II and sequestosome 1, by blocking autophagic flux. By blocking autophagy flux, 053 suppressed proliferation, induced apoptosis and ultimately restored chemosensitivity in MDA‑MB‑231 cells. In addition, the MDA‑MB‑231 xenograft model indicated that 053 inhibited autophagy by blocking autophagic flux, which lead to the accumulation of LC3 and sequestosome 1. 053 also negatively regulated the expression of programmed death‑ligand 1 (PD‑L1) in tumor cells. The 4T1 xenograft model showed that 053 had a notable immune‑promoting effect, whereby it not only negatively regulated the expression of PD‑L1 in tumor cells but also modulated T cell activation and proliferation by downregulating the expression of co‑inhibitory molecules (T‑cell immunoglobulin and mucin‑domain containing‑3 and programmed cell death protein 1) on T cells and upregulating co‑stimulatory molecules (4‑1BB, OX40 and inducible T‑cell co‑stimulator). In vivo xenograft models demonstrated that 053 had notable antitumor effects and high biosafety, with improved antitumor efficacy when combined with the chemotherapy drug gemcitabine. In summary, 053 can block autophagy and promote antitumor immune responses, showing promise as a new generation of adjuvant drugs for tumor chemotherapy and immunotherapy.

Here we report a highly efficient method for coupling of peroxypyrroloindolenines with amines under catalyst-free conditions to obtain stable C2-N peroxyindolenines in high yields with remarkable functional group tolerance. Initial studies have shown that compound 13 exhibits potent inhibition of the B16/F10 cell line with an IC50 value of 2.18 μM.

Ferrocene, known for its 'sandwich' structure and Fenton catalytic activity for tumor treatment, its twodimensional (2D) self-assembly has not yet been exploited for therapeutic applications. Perfluorocarbons (PFCs) can carry and transport oxygen to alleviate tumor hypoxia. Nevertheless, designing ferrocene derivatives with PFC chains to alleviate tumor hypoxia and improve cancer treatment remains a challenge. Here, we first synthesized ferrocene derivatives with different PFC chains (nF-Fc, n = 5, 9, 13) by conjugating perfluorocarbonic acids with 2-(ferrocenylethynyl)aniline (Fc). These derivatives were able to self-assemble into 2D nanosheets, with hydrated particle size decreasing as the chain length increased. The chain lengths also influenced the oxygen-carrying capacity, iron release capacity, and glutathione consumption capacity, all of which impacted their ability to alleviate tumor hypoxia, produce intracellular reactive oxygen species, and enhance chemodynamic therapeutic efficacy. Notably, PFC incorporation altered the mechanism of induced cell death. By elucidating the effects of ferrocene derivatives with different PFC chains on the hypoxic tumor microenvironment (TME) and their therapeutic efficacy, this research advances the development of ferrocene-based 2D materials for cancer treatment and offers a novel approach to optimize compound structures better regulation of the hypoxic TME, ultimately improving therapeutic outcomes.

Heptamethine indocyanine dyes (HMICDs) have excellent near-infrared (NIR) properties and are capable of converting light energy into heat energy under NIR laser irradiation, enabling their use in photothermal therapy (PTT) of tumors. However, their photostability is poor, and they are easily inactivated by photobleaching after prolonged and repeated exposure to NIR laser. In addition, unmodified HMICDs have poor water solubility and tend to aggregate, limiting their biological applications. Herein, we designed and synthesized HMICDs with hydrophilic side chains and different substituent groups on polymethine chain, and explored the effects of these modifications on the water solubility, photostability and photothermal properties of the dyes. The introduction of tri-ethylene glycol hydrophilic side chains can improve the water solubility of HMICDs, and enhance the photostability and photothermal properties by increasing the spatial hindrance of the dyes. Furthermore, the incorporation of substituents with strong electron-withdrawing ability into the polymethine chain can improve the photostability and photothermal effect of the dyes. Under laser irradiation, the dyes can inhibit the proliferation of tumor cells by enhancing intracellular reactive oxygen species levels, decreasing mitochondrial membrane potential, and inducing cell apoptosis. In two tumor-bearing mouse models, dye 11 can effectively inhibit tumor growth by exerting photothermal effects with good biosafety. This work can provide a research foundation for the subsequent construction of HMICDs-based photothermal therapeutic agents for clinical applications.

Reactive oxygen species (ROS)-based nanodynamic therapy is emerging as a promising approach for tumor treatment, particularly in eliciting immune responses for tumor immunotherapy. Nevertheless, the complex tumor microenvironment (TME) and the constraints of current sensitizers substantially compromise therapeutic efficacy. To address these challenges, we developed a rationally designed nanoplatform (LP/CuTT) through lipoic acid-modified orchestrated Cu²⁺-coordinated tetracycline-porphyrin self-assembly, to precisely remodel the immunosuppressive TME while potentiating antitumor immunotherapy via a novel photo-enhanced chemodynamic therapy (CDT) strategy. In vitro studies demonstrated that LP/CuTT-mediated photo-enhanced CDT effectively promoted concurrent apoptosis and cuproptosis in B16-F10 melanoma cells, coupled with robust induction of immunogenic cell death (ICD). Mechanistic investigations revealed that LP/CuTT drives macrophage polarization from tumor-promoting M2 to antitumor M1 phenotypes while promoting dendritic cell (DC) maturation, thereby orchestrating potent antitumor immune responses. In vivo evaluations showed preferential tumor accumulation of LP/CuTT, correlating with substantial ROS generation at tumor sites and remarkable therapeutic outcomes. Quantitative assessments further demonstrated elevated M1 macrophage infiltration in both tumor and splenic tissues, accompanied by enhanced CD8+ and CD4+ T cell recruitment. These findings provide key insights into developing orchestrated metal-coordinated nanotherapeutics by repurposing existing therapeutic agents, enabling the design of multifunctional systems that integrate efficient chemodynamic activity, TME remodeling, and immune activation for effective nanodynamic therapy.

Inorganic antimicrobial materials have the advantages of high safety, strong durability, stable antimicrobial performance, and good heat resistance compared with organic antimicrobial materials. In this study, Fe-doped small zinc oxide nanoparticles (FZO-NPs) with different iron contents were synthesized and then modified with 3-aminopropyltriethoxysilane (APTES) and poly(ethylene glycol)-600 (PEG-600) to afford FZO-APs. FZOAPs which were fully characterized can disperse in water with good dispersity and improved stability. In antimicrobial tests, FZO-AP4 displayed excellent antimicrobial effects under 10 min of 365 nm UV light against Gram-negative bacteria Escherichia coli (E. coli) and Gram-positive bacteria Staphylococcus aureus (S. aureus) with a minimum inhibitory concentration (MIC) of 0.20 and 0.15 mg/mL, respectively. The antimicrobial mechanism studies revealed that the consumption of glutathione (GSH) and ascorbic acid (ASA), and the generation of reactive oxygen species (ROS) could trigger lipid peroxidation (LPO) and ultimately induce ferroptosis in bacterial cells. The cause of the cell wall/membrane damage and the released Zn/Fe ions from the nanoparticles inside the bacterial cells further promote the antimicrobial effects. In addition, FZO-AP4 showed high inhibitory effects on bacterial biofilm formation and significantly disrupted the formed biofilm. Interestingly, higher bacterial biofilm residuals and bacterial survival were found in E. coli than in S. aureus after FZO-AP4 treatment, suggesting a potential link between the quorum sensing (QS) system of the bacteria and their different susceptibility towards FZO-AP4. This study proved the antibacterial effects of small water-soluble FZO-APs which is meaningful for the design and development of new inorganic nano-material for antimicrobial applications.