Owing to high antibiotic resistance and thermotolerance, bacterial biofilm infections (BBIs) are refractory to elimination. Iron is essential for bacterial growth and metabolism, and bacteria can thus accumulate iron from surrounding cells to maintain biofilm formation and survival. Consequently, iron deficiency in the biofilm microenvironment (BME) leads to the functional failure of innate immune cells. Herein, a novel antibiofilm strategy of iron‐actuated Janus ion therapy (IJIT) is proposed to regulate iron metabolism in both bacterial biofilm and immune cells. A BME‐responsive photothermal microneedle patch (FGO@MN) is synthesized by the growth of Fe₃O₄ nanoparticles on graphene oxide nanosheets and then encapsulated in methacrylated hyaluronic acid needle tips. The catalytic product of ·OH by FGO@MN in BME disrupts the bacterial heat‐shock proteins, coercing biofilm thermal sensitization. As synergistic mild photothermal treatment triggers iron uptake, the intracellular iron overload further induces ferroptosis‐like death. Moreover, iron‐nourished neutrophils around BME can be rejuvenated for reactivating the suppressed antibiofilm function. Thus, more than 95% BBIs elimination can be achieved by combining heat stress‐triggered iron interference with iron‐nutrient immune reactivation. Furthermore, in vivo experiments validate the scavenging of refractory BBI after 15 days, suggesting the promising perspective of IJIT in future clinical application.

Poor wound healing after diabetes mellitus remains a challenging problem, and its pathophysiological mechanisms have not yet been fully elucidated. Persistent bleeding, disturbed regulation of inflammation, blocked cell proliferation, susceptible infection and impaired tissue remodeling are the main features of diabetic wound healing. Conventional wound dressings, including gauze, films and bandages, have a limited function. They generally act as physical barriers and absorbers of exudates, which fail to meet the requirements of the whol diabetic wound healing process. Wounds in diabetic patients typically heal slowly and are susceptible to infection due to hyperglycemia within the wound bed. Once bacterial cells develop into biofilms, diabetic wounds will exhibit robust drug resistance. Recently, the application of stimuli-responsive hydrogels, also known as “smart hydrogels”, for diabetic wound healing has attracted particular attention. The basic feature of this system is its capacities to change mechanical properties, swelling ability, hydrophilicity, permeability of biologically active molecules, etc., in response to various stimuli, including temperature, potential of hydrogen (pH), protease and other biological factors. Smart hydrogels can improve therapeutic efficacy and limit total toxicity according to the characteristics of diabetic wounds. In this review, we summarized the mechanism and application of stimuli-responsive hydrogels for diabetic wound healing. It is hoped that this work will provide some inspiration and suggestions for research in this field.

There is an increasingly growing demand for nonantibiotic strategies to overcome drug resistance in bacterial biofilm infections. Here, a novel “gas-sensitized hyperthermia” strategy is proposed for appreciable bacteria killing by the smart design of a metal-organic framework (MOF)–sealed Prussian blue–based nanocarrier (MSDG). Once the biofilm microenvironment (BME) is reached, the acidity-activated MOF degradation allows the release of diallyl trisulfide and subsequent glutathione-responsive generation of hydrogen sulfide (H ₂ S) gas. Upon near-infrared irradiation, H ₂ S-sensitized hyperthermia arising from MSDG can efficiently eliminate biofilms through H ₂ S-induced extracellular DNA damage and heat-induced bacterial death. The generated H ₂ S in the biofilm can stimulate the polarization of macrophages toward M2 phenotype for reshaping immune microenvironment. Subsequently, the secretion of abundant regeneration-related cytokines from M2 macrophages accelerates tissue regeneration by reversing the infection-induced pro-inflammatory environment in an implant-related infection model. Collectively, such BME-responsive nano-antibacterials can achieve biofilm-specific H ₂ S-sensitized thermal eradiation and immunomodulatory tissue remodeling, thus realizing the renaissance of precision treatment of refractory implant–related infections.

Implant-associated infection (IAI) is increasingly emerging as a serious threat with the massive application of biomaterials. Bacteria attached to the surface of implants are often difficult to remove and exhibit high resistance to bactericides. In the quest for novel antimicrobial strategies, conventional antimicrobial materials often fail to exert their function because they tend to focus on direct bactericidal activity while neglecting the modulation of immune systems. The inflammatory response induced by host immune cells was thought to be a detrimental force impeding wound healing. However, the immune system has recently received increasing attention as a vital player in the host’s defense against infection. Anti-infective strategies based on the modulation of host immune defenses are emerging as a field of interest. This review explains the importance of the immune system in combating infections and describes current advanced immune-enhanced anti-infection strategies. First, the characteristics of traditional/conventional implant biomaterials and the reasons for the difficulty of bacterial clearance in IAI were reviewed. Second, the importance of immune cells in the battle against bacteria is elucidated. Then, we discuss how to design biomaterials that activate the defense function of immune cells to enhance the antimicrobial potential. Based on the key premise of restoring proper host-protective immunity, varying advanced immune-enhanced antimicrobial strategies were discussed. Finally, current issues and perspectives in this field were offered. This review will provide scientific guidance to enhance the development of advanced anti-infective biomaterials.

The formation of biofilms is closely associated with persistent and chronic infections, and physiological heterogeneity such as pH and oxygen gradients renders biofilms highly resistant to conventional antibiotics. To date, effectively treating biofilm infections remains a significant challenge. Herein, we report the fabrication of micellar nanoparticles adapted to heterogeneous biofilm microenvironments, enabling nitric oxide (NO) release through two distinct photoredox catalysis mechanisms. The key design feature involves the use of tertiary amine (TA) moieties, which function as sacrificial agents to avoid the quenching of photocatalysts under normoxic and neutral pH conditions and proton acceptors at acidic pH to allow deep biofilm penetration. This biofilm-adaptive NO-releasing platform shows excellent antibiofilm activity against ciprofloxacin-resistant Pseudomonas aeruginosa (CRPA) biofilms both in vitro and in a mouse skin infection model, providing a strategy for combating biofilm heterogeneity and biofilm-related infections.