Chronic wounds are life-threatening conditions characterized by impaired closure. Chronic inflammation and impaired regeneration and repair lead to the pathological phenotype of chronic diabetic wounds and reduce drug efficacy. In this study, we found that the poor proliferative and differentiative ability of epidermal stem cells (EpSCs) within an inflammatory microenvironment is a key factor contributing to the delayed healing of chronic diabetic wounds. To address this issue, we designed a nanocascade engineering workshop (Cu5.4O@LL-37/pDNA) capable of simultaneously reshaping the inflammatory microenvironment and activating EpSC functions to promote rapid wound closure. The workshop used a core-shell structure design. The core, an ultrasmall Cu5.4O nanozyme, can efficiently eliminate reactive oxygen species, enhance the inflammatory response, and transform the pathological wound microenvironment into a niche facilitating regeneration. The shell is constructed through the electrostatic assembly of plasmid DNA (pDNA) and the antibacterial peptide LL-37, enhancing gene transfection efficiency and inhibiting bacterial infection effectively. By leveraging its dual advantages in microenvironment modulation and structural design, the system substantially improves gene delivery and facilitates sustained P311 expression, thereby promoting EpSC proliferation and differentiation. This nanotherapy reshaping the microenvironment and activating EpSC function accelerates re-epithelialization and wound closure in both diabetes and infection models. This treatment strategy is a novel approach to achieve durable and effective healing in chronic wounds.

Developing biomimetic asymmetric wound dressings that mimic the structure and multifunctionality of natural skin remains challenging. Here, we report a natural polysaccharide-based asymmetric hydrogel (MP/AMBGZ) derived from Bletilla striata polysaccharide (BSP) via a facile one-pot, two-step strategy. Methacrylated BSP forms a biocompatible network, while gallic acid provides wet adhesion and antioxidant activity. ZnO nanoparticles incorporated into the inner layer enable Zn2+-mediated antibacterial activity and promote angiogenesis. Meanwhile, the outer MA-POSS layer forms a hydrophobic barrier that prevents bacterial adhesion. The hydrogel exhibits good mechanical properties, high swelling capacity, and excellent biocompatibility. In vitro studies demonstrate its cytocompatibility, antibacterial activity, hemostatic performance, and anti-inflammatory effects. In vivo experiments show rapid hemostasis and accelerated wound healing. In infected full-thickness wounds, MP/AMBGZ achieves near-complete closure within 14 days and promotes functional skin regeneration, including hair follicle formation. Overall, this work highlights the potential of BSP-based asymmetric hydrogels as multifunctional wound dressings for clinical applications.

Treponema pallidum subsp. pallidum (T. pallidum), the causative agent of syphilis, disseminates to distant organs by disrupting the vascular endothelial barrier, yet the underlying molecular mechanisms remain poorly understood. Here, we investigated the role of the serine protease Tp0841 in this process. Bioinformatics and immunofluorescence localized Tp0841 to the periplasmic space of T. pallidum. Recombinant Tp0841 (rTp0841) and a catalytically inactive mutant (rΔTp0841) were generated. rTp0841 exhibited no cytotoxicity toward human endothelial cells (HUVEC and hCMEC/D3). Nonetheless, it induced concentration- and time-dependent downregulation of the tight junction protein ZO-1 and the adherens junction protein VE-cadherin, leading to reduced transendothelial electrical resistance and increased permeability. Occludin expression was unaffected, and rΔTp0841 had no effect on any of these proteins. Molecular docking and in vitro cleavage assays confirmed that Tp0841 directly proteolytically processes ZO-1 and VE-cadherin. Collectively, these findings demonstrate that Tp0841 directly degrades ZO-1 and VE-cadherin to disrupt vascular barrier integrity, thereby facilitating bacterial dissemination. Tp0841 thus represents a previously unrecognized virulence determinant contributing to the systemic spread of T. pallidum.

The enzyme activity of redox-related selenoproteins is impaired post-tissue injury or inflammation, exacerbating oxidative stress and apoptosis. In this study, we present a strategy using selenotrisulfide (STS) to enhance the selenium content and restore selenoprotein-like activity in vivo via thiol-exchange reactions. The exact mass-to-charge ratio (m/z) change was observed at cysteine residue sites by liquid chromatography-mass spectroscopy (LC-MS), demonstrating the feasibility of the thiol-exchange reaction and the modification of selenium with proteins. Compared to the traditional selenium sources such as sodium selenite (Na2SeO3), L-selenomethionine (SeMet) and L-selenocysteine ((Sec)2), STS exhibited superior antioxidative and therapeutic efficacy by augmenting selenium levels and oxidoreductase-like activities in vitro and in vivo. Proteomic analysis revealed that STS could better improve myocardial contraction and regulate glucolipid metabolism to enhance energy supply and cardiac repair. Furthermore, the core-shell nanofibrous ZPB@STS patch significantly contributed to lower inflammatory response, less cell death and collagen deposition, and stronger cardiac contraction through the cooperative interaction of selenium-regulation from STS and mechanical support from the elastomeric polyurethane fibrous patch.

Acute kidney injury (AKI) is a life-threatening disorder that is responsible for 1.7 million deaths each year. Current treatment strategies, such as renal replacement therapy and supportive care, remain ineffective in reversing tubular damage in 20–50

600 Background: The KEYNOTE-522 and IMpassion031 trials established that adding immune checkpoint inhibitors to neoadjuvant chemotherapy significantly improves pathologic complete response (pCR) rates and survival outcomes in triple-negative breast cancer (TNBC). In our previously reported phase II NeoTAPPL trial, an anthracycline-free neoadjuvant regimen of penpulimab (anti-PD-1 antibody), carboplatin, and taxanes demonstrated promising efficacy and manageable safety. Here, we present updated efficacy and safety outcomes from the full trial cohort. Methods: In this open-label, multi-center phase II study, patients with untreated, histologically confirmed TNBC in stage II-III were enrolled. Patients received 6 cycles of neoadjuvant therapy with penpulimab (200 mg, d1, q3w) plus taxanes (docetaxel 75 mg/m2 or nab-paclitaxel 260 mg/m2, d1, q3w) and carboplatin (AUC=6, d1, q3w). Patients who either completed or discontinued the neoadjuvant treatment would undergo breast surgery. Adjuvant chemotherapy and immunotherapy were at the discretion of the treating physician, and radiation therapy was per standard of care. The primary endpoint was the rate of pCR based on the definition of ypT0/Tis ypN0. Secondary endpoints included residual cancer burden (RCB), event free survival (EFS), overall survival (OS), adverse events (AE), and immune response biomarkers. Results: 64 patients were enrolled, all of whom received neoadjuvant treatment and underwent surgery. The median age was 53 years (range, 32-73). At diagnosis, 54 patients (84.4%) had stage II disease. pCR was achieved in 41 of 64 patients (64.1%; 95% CI, 51.1%-75.7%), and 50 patients (78.1%; 95% CI, 66.0%-87.5%) achieved RCB 0-1. The objective response rate (ORR) and disease control rate (DCR) were 93.8% (95% CI, 84.8%-98.3%) and 98.4% (95% CI, 91.6%-100%), respectively. Subgroup analyses revealed pCR rates of 64.8% (35/54) in patients with stage II disease and 60.0% (6/10) in those with stage III disease. The pCR rate was 64.9% (24/37) in node-negative patients and 63.0% (17/27) in node-positive patients. Treatment-emergent adverse events (TEAEs) of any grade occurred in all 64 patients, with grade ≥3 TEAEs reported in 24 patients (37.5%). The most common grade ≥3 TEAEs were alopecia (20.3%), anemia (14.1%), neutropenia (10.9%), and leukopenia (10.9%). Conclusions: The NeoTAPPL trial demonstrates that an anthracycline-free neoadjuvant regimen is an effective and tolerable treatment strategy for patients with TNBC. The regimen achieved a high pCR rate, which remained consistent across key prognostic subgroups, including disease stage and nodal status. The safety profile was manageable, with no new safety signals identified. Clinical trial information: ChiCTR2300071925 .

Ultrasound-targeted nanobubble destruction (UTND) is a promising noninvasive strategy for cancer treatment. However, off-target effects significantly influence UTND-mediated therapeutic efficacy and compromise accurate evaluation of tumors. Prostate-specific membrane antigen (PSMA) is overexpressed on the membranes of prostate cancer (PCa) cells, making it a key therapeutic target. In this study, we constructed theranostic-targeted nanobubbles (PSMA-617-ICG NBs) incorporating PSMA-617, a clinical small-molecule inhibitor of PSMA, and indocyanine green (ICG) employing mechanical vibration in conjunction with a biotin-avidin coupling strategy. PSMA-617-ICG NBs were selectively extravasated across the tumor vascular endothelium, bound to PSMA-positive cells and accumulated effectively within the tumor tissue. Under ultrasound irradiation, sufficient number of PSMA-617-ICG NBs adhered to the cell surface and generated close-range shock waves and cavitation, significantly destroying tumor cells and inhibiting PCa growth. Meanwhile, ultrasound, photoacoustic, and fluorescence imaging enabled monitoring of PSMA expression in tumor tissues, potentially providing imaging evidence to support UTND-mediated targeted therapy and assisting in tumor localization. Notably, mechanistic investigations revealed enhanced autophagosome formation and increased autophagosome-lysosome fusion in treated cells, indicating that UTND successfully activated autophagy and exerted an anti-tumor effect by inducing autophagy-related cell death. Therefore, this study demonstrates that the feasibility of using targeted multimodal imaging nanobubbles in combination with ultrasound irradiation as a potential therapeutic strategy for PCa. STATEMENT OF SIGNIFICANCE: This work presents prostate specific membrane antigen (PSMA)-targeted nanobubbles (PSMA-617-ICG NBs) that integrate multimodal imaging with ultrasound-triggered therapy for prostate cancer. Its significance lies in overcoming the off-target effects of conventional ultrasound targeted nanobubble destruction (UTND) through precise molecular targeting, and realizing ultrasound/photoacoustic/fluorescence imaging-guided therapy. Under ultrasound irradiation, the targeted nanobubbles successfully activate autophagy and exert an anti-tumor effect through inducing autophagy-related cell death. The targeted nanobubbles demonstrate specific accumulation in PSMA-positive tumors, monitoring therapy, and significantly amplified therapeutic efficacy against prostate cancer, bringing a non-invasive, promising approach for prostate cancer therapy.

Objective: This study investigates the therapeutic potential of cold atmospheric plasma (CAP) in promoting chronic wound healing in diabetic mice and explores the associated cellular responses. Methods: In vitro experiments were conducted using HaCaT and RAW 264.7 cells to evaluate the effects of CAP on cell viability, migration, and proliferation. Transcriptomic analysis was performed in RAW 264.7 cells to identify CAP-induced gene expression changes. In vivo, a streptozotocin-induced diabetic mouse model with full-thickness skin wounds was treated with CAP for 0 s- 40 s, and wound healing was assessed through histological and immunohistochemical analyses. Results: CAP treatment significantly enhanced cell viability, migration, and proliferation in vitro. RNA sequencing revealed enrichment of genes associated with DNA replication and cell cycle regulation. In diabetic mice, CAP treatment accelerated wound closure and promoted re-epithelialization, collagen deposition, and cellular proliferation at the wound site. Conclusion: CAP treatment promotes diabetic wound healing by enhancing cellular proliferation and migration while modulating local inflammatory responses. Significance: These findings support CAP as a promising non-invasive therapeutic strategy for chronic diabetic wound management.

Adjuvant skincare formulations possessing anti-inflammatory and antibacterial properties can alleviate treatment-related side effects and enhance patient adherence in acne management. Paeonol (PAE), totarol (TOT), and ergothioneine (ERG) demonstrate promising anti-acne activity. However, their clinical translation is hindered by poor solubility, limited stability, and insufficient skin permeation. To address these limitations, we coencapsulated PAE, TOT, and ERG into hyaluronic acid (HA)-modified nanoliposomes (NLPs). Compared to the NLPs modified with HA with high-molecular-weight, those formulated with miniHA (3-10 kDa) exhibited superior skin penetration capability and cellular uptake efficiency. The miniHA modified NLPs co-encapsulated PAE, TOT, and ERG (PTE-NLPs) exhibited excellent biocompatibility in both in vitro cytotoxicity and chicken embryo chorionic allantoic membrane irritation assays. Compared to free functional ingredients, PTE-NLPs demonstrated significantly enhanced anti-inflammatory and antibacterial efficacy in cellular assays. Furthermore, in 3D skin models, PTE-NLPs suppressed Transient Receptor Potential Vanilloid 1 (TRPV1) expression, indicating a potential mechanism for attenuating neuronal hyperreactivity. The anti-inflammatory activity was subsequently validated in vivo. These findings collectively demonstrate that miniHA-modified NLPs provide a safe and efficient platform for co-delivering synergistic anti-acne actives, highlighting their strong potential as an adjuvant therapy for acne management.

Rheumatoid arthritis (RA) is a chronic autoimmune disease, and current antirheumatic drugs have poor efficacy or cause considerable systemic adverse reactions. Neutrophil activation is a central driver of RA pathogenesis; however, approaches that curb pathogenic neutrophil activity while preserving host defense are lacking. In patients with RA, we identified spleen tyrosine kinase (SYK) as a key upstream regulator whose aberrant activation drives neutrophil hyperactivation, neutrophil extracellular trap (NET) formation, inflammatory mediator release, and delayed apoptosis, while preserving antimicrobial function. Moreover, we engineered a HSA-AAPV-TKI (HAT) nanodrug by conjugating human serum albumin (HSA) to a SYK-targeted tyrosine kinase inhibitor (TKI) via a neutrophil elastase-cleavable AAPV peptide linker (Ala-Ala-Pro-Val). HAT is preferentially internalized by circulating neutrophils in CIA mice, traffics with them to inflamed joints, and releases the inhibitor in response to local neutrophil activation, thereby attenuating SYK signaling and pathogenic neutrophil functions while largely preserving antimicrobial activity. In a collagen-induced arthritis mouse model, HAT significantly reduced joint swelling, arthritis scores, and structural joint damage without impairing host defense. This strategy establishes a new RA therapeutic avenue that reconciles potent efficacy with immune safety and represents a milestone toward translational neutrophil-targeted therapy.

Extracellular vesicles (EVs) have emerged as promising vectors for precision therapeutic applications owing to their unique inherent ability to target specific cells and tissues. This review explores the multifaceted role of EVs in disease therapy, focusing on their natural targeting abilities and potential for enhancing therapeutic agent delivery. This review focuses on the inherent targeting mechanisms of EVs and their application in antitumor strategies, anti-inflammatory therapies, tissue repair, and immune modulation. Moreover, it surveys the innovative bioengineering strategies that can improve the efficiency with which cargo is loaded into EVs, techniques for engineering EVs to achieve precision delivery of their cargo, and strategies for scalable EV production. Finally, challenges, such as scalability, standardization, and biosafety, still need to be addressed. This review provides a forward-looking perspective on the role of EVs in clinical settings, emphasizing their importance in the development of precise and potent treatment strategies.

Chemotherapy combined with immunotherapy is a highly promising approach for treating tumors. However, chemotherapeutic drugs often fail to accumulate effectively at the tumor site after systemic administration and they lack sufficient immunogenicity to activate adaptive immunity, making an effective T-cell immune response within the tumor microenvironment difficult to achieve. Here, this work developed drug-loaded nanobubbles (DTX-R837@NBs) that encapsulate the chemotherapy drug docetaxel and the immune adjuvant R837 via a thin-film hydration method. Ultrasound-targeted nanobubble destruction promoted drug accumulation within tumor tissues and damaged tumor cells through the cavitation effect, inducing immunogenic cell death and releasing damage-associated molecular patterns to augment dendritic cell maturation. Notably, DTX-R837@NBs exhibited excellent contrast-enhanced ultrasound imaging capabilities, enabling the seamless integration of diagnosis and treatment. In combination with immune checkpoint blockade targeting programmed cell death protein 1 (PD-1), the generated immunological responses attacked residual tumor cells and ameliorated the immunosuppressive tumor microenvironment, inhibiting distant tumor growth and metastasis. Moreover, this strategy exhibited robust immune memory effects, effectively protecting the host and preventing tumor recurrence upon rechallenge. Overall, ultrasound-mediated DTX-R837@NBs combined with anti-PD-1 immune checkpoint blockade therapy exhibits robust antitumor efficiency, represent a promising strategy for overcoming immunotherapy resistance in cold tumors, and warrant further investigation for clinical translation.

Acute respiratory distress syndrome (ARDS) is a lethal respiratory condition, while effective pharmacological treatments remain elusive. We identified the decreased mechanical capacity and impaired proliferation of alveolar type 2 (AT2) epithelial cells in the inflammatory environment as the primary contributors to respiratory failure of ARDS. A biomimetic, self-adaptive, 7,8-dihydroxyflavone-loaded hollow mesoporous cerium oxide coated with a platelet membrane (HCeOx-D@PM) was developed for precise ARDS therapy. HCeOx-D@PM comprises a platelet membrane (PM) shell for targeted delivery to injured lungs and an HCeOx core, which enables high drug loading, efficient reactive oxygen species (ROS) scavenging, and penetration of the alveolar-capillary barrier. Initially, HCeOx-D@PM suppresses the inflammation and mitigates the adverse effects of lesions on AT2 cell by scavenging accumulated ROS. It then adaptively releases 7,8-dihydroxyflavone in response to cysteine-aspartic acid protease 3 activation, facilitating AT2 cell proliferation and notably improving survival rates in vivo, offering a promising advancement in the precise treatment of respiratory diseases.

Excessive oxidative stress and dysregulated macrophage polarization-characterized by M1/M2 imbalance-drive chronic, persistent inflammation and represent key pathological mechanisms underlying impaired tissue repair in diabetic wounds; however, therapeutic strategies targeting both these processes remain limited. L-arginine (L-Arg) shows therapeutic potential through its antioxidant properties and ability to promote M1 macrophage polarization. Nevertheless, the mechanisms by which L-Arg regulates mitochondrial homeostasis to exert antioxidant effects remain unclear. Moreover, its clinical translation is hindered by poor retention, inadequate tissue penetration and damage induced by hypertonicity, thereby necessitating the development of innovative delivery systems. To address these limitations, we developed an L-Arg-loaded microneedle (L-Arg-MN) patch for controlled delivery. Our findings demonstrate that L-Arg alleviated hydrogen peroxide (H2O2)-induced cellular damage through activation of the Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase-1 (HO-1) pathway, boosting antioxidant enzyme (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px)) and lowering malondialdehyde (MDA) levels. Mechanistically, L-Arg maintained mitochondrial homeostasis by upregulating peroxiredoxin 1 (PRDX1) expression, restoring mitochondrial membrane potential and enhancing adenosine triphosphate production. Furthermore, L-Arg suppressed M1 macrophage polarization and promoted M2 polarization through PRDX1-mediated mitochondrial metabolic pathways. In models of diabetic wounds, the L-Arg-MN patch markedly enhanced the wound healing process, accelerated wound closure, reduced concentration of reactive oxygen species (ROS), enhanced granulation tissue, collagen formation and increased M2 macrophage infiltration. This study elucidates how L-Arg reduces oxidative stress and enhances M2 macrophage polarization by regulating mitochondrial metabolism through the PRDX1 pathway. By integrating the metabolic and immunomodulatory properties of L-Arg with advanced drug delivery technology, the L-Arg-MN patch presents an innovative and efficient approach to treating diabetic wounds.

Acute kidney injury (AKI) is a global health challenge responsible for approximately 1.7 million deaths each year. Current treatment options, such as renal replacement therapy and supportive care, are limited to systemic support and fail to promote repair of dysfunctional renal tubular epithelial cells (RTECs). In this study, we developed a macrophage membrane-coated sequential-targeting nanodrug, MA-5@MΦ-LSALT, which leverages the LSALT targeting peptide to selectively deliver the nanodrug to injured RTECs. Upon reaching the damaged RTECs, the released mitochonic acid-5 (MA-5) further localizes to mitochondria. In both cisplatin-induced and ischemia-reperfusion AKI models, MA-5@MΦ-LSALT inhibited calcium influx and reduced reactive oxygen species levels. Collectively, this work introduces an innovative sequential-targeting strategy from kidneys to RTECs to mitochondria that effectively addresses the challenge of targeted repair in AKI and highlights a promising therapeutic avenue for clinical translation.

Acute kidney injury (AKI) occurs when there is an imbalance in the immune microenvironment, leading to ongoing and excessive inflammation. Numerous immunomodulatory therapies have been suggested for the treatment of AKI, the current immunomodulatory treatment delivery systems are suboptimal and lack efficiency. Given the lack of effective treatment, AKI can result in multi-organ dysfunction and even death, imposing a significant healthcare burden on both the family and society. This underscores the necessity for innovative treatment delivery systems, such as nanomaterials, to better control pathological inflammation, and ultimately enhance AKI treatment outcomes. Despite the modification of numerous immunomodulatory nanomaterials to target the AKI immune microenvironment with promising therapeutic results, the literature concerning their intersection is scarce. In this article, the pathophysiological processes of AKI are outlined, focusing on the immune microenvironment, discuss significant advances in the comprehension of AKI recovery, and describe the multifunctionality and suitability of nanomaterial-based immunomodulatory treatments in managing AKI. The main obstacles and potential opportunities in the swiftly advancing research field are also clarified.

Amidst rising antimicrobial resistance, bacteriophage (phage) therapy has re-emerged as a pivotal weapon against multidrug-resistant pathogens. Jumbo phages, distinguished by large genomes, show particular therapeutic promise. Yet current understanding of jumbo phages is still lacking. Phage was isolated from domestic sewage. The biological properties of JP4 was characterized via transmission electron microscopy, stability tests, one-step growth curve. The genome of JP4 were elucidated by sequencing and bioinformatics tools. Structural proteins were identified via mass spectrometry. Bactericidal and biofilm eradication activities were evaluated using bacterial turbidity measurements and crystal violet assays, respectively. Statistical significance was determined by using one-way ANOVA in GraphPad Prism. Phage JP4 has an icosahedral head (approximately 110 nm in diameter) and a contractile tail (about 120 nm in length). JP4 possesses a linear dsDNA genome of 370,741 bp, encoding 738 proteins and 8 tRNAs. Phylogenetic analysis revealed that JP4 is a new member of the Asteriusvirus genus, and shares close evolutionary relationships with Escherichia phage UB. Additionally, mass spectrometry identified four novel structural protein encoding genes of JP4. Phage JP4 exhibited rapid infection cycle, high stability, potent in vitro bactericidal activity, and strong inhibitory effect on E. coli biofilms. Phage JP4 is a new member of the Asteriusvirus genus. As a lytic jumbo phage with rapid bactericidal activity and strong biofilm degradation capacity, JP4 is a promising therapeutic candidate against E. coli O157:H7 infections. This study provides insights into the diversity and clinical potential of jumbo phages in combating pathogens.

Ultrasound-targeted micro/nanobubble cavitation (UTMC/UTNC) has emerged as a highly promising ultrasound-based strategy for precision tumor therapy. This technique harnesses microbubbles and nanobubbles as cavitation nuclei that respond to ultrasound, inducing cavitation effects, generating mechanical forces that transiently permeabilize biological barriers, enhance vascular and cellular permeability, and induce localized tumor cell disruption. These cavitation-mediated effects enable spatiotemporally controlled drug release, markedly improving intratumoral drug accumulation and maximizing therapeutic efficacy while reducing systemic toxicity. This review provides a comprehensive overview of the mechanistic foundations and therapeutic applications of UTMC/UTNC. The physical mechanisms by which bubbles act as cavitation nuclei, undergoing oscillation, expansion, collapse, or rupture under ultrasound stimulation, and their resulting biological effects are discussed in detail. Furthermore, emphasizing the roles of UTMC/UTNC in enhancing chemotherapy, sonodynamic therapy, immunotherapy, gene delivery, radiotherapy, and ferroptosis is reviewed. These therapeutic enhancements are primarily attributed to improved drug delivery and cavitation-induced tumor cell disruption. Finally, key challenges and limitations associated with UTMC/UTNC-mediated tumor therapy are discussed, along with prospects for clinical translation.

The evolutionary arms race between bacterial immunity and phages has driven the emergence of sophisticated anti-defense systems (ADSs). However, certain ADSs exhibit incomplete suppression of their cognate defense systems, suggesting functional cooperation between multiple ADSs targeting the same bacterial safeguard. In this study, we characterize Dap2, a protein encoded by a Pseudomonas aeruginosa phage PaoP5, which directly binds to the Lon protease to prevent the degradation of the phage-encoded HNH endonuclease. Deletion of dap2 in PaoP5 exhibits significantly impaired genome packaging due to insufficient levels of HNH. Strikingly, Dap2 synergizes with its genomically adjacent partner Dap1, a previously identified HNH-binding protein providing partial Lon resistance, to achieve complete protection of HNH. Beyond anti-defense activity, Dap2 disrupts host virulence by sequestering the type III secretion system (T3SS) transcriptional activator ExsA, suppressing bacterial pathogenicity while redirecting metabolic resources toward phage progeny production. This study unveils a dual functional ADS that simultaneously modulates bacterial virulence and anti-phage immunity, both aimed at ensuring phage survival and maximizing progeny production. Furthermore, it elucidates a novel mechanism whereby phages employ synergistic ADS pairs (Dap1/Dap2) to achieve complete neutralization of a bacterial defense system, when individual components provide only partial protection. These findings significantly enhance our understanding of the intricate evolutionary arms race between phages and their bacterial hosts.