Mingzhou Ye

Chronic lung graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains difficult to treat, and broad immunosuppression increases infection risk. Single-cell profiling of bronchoalveolar lavage from bronchiolitis obliterans lesions revealed collapse of an epithelial nicotinamide adenine dinucleotide (NAD ⁺ ) metabolic axis with pathogenic immune-epithelial remodeling, nominating NAD ⁺ restoration as an entry point. Because free NAD ⁺ is poorly cell-permeable and rapidly consumed, we engineered CaNAD ⁺ -PGB-LiP (CNAPL), a high-payload NAD ⁺ nanomedicine enabling direct intracellular replenishment. In murine allo-HSCT GVHD, CNAPL improved clinical scores and survival, reduced vascular and epithelial injury, and curtailed hyperinflammation and effector overactivation across GVHD target organs. Unlike immunosuppression, CNAPL preserved phagocytosis, NK/NKT cell (natural killer/natural killer T cell) cytotoxicity, and T cell memory. In posttransplant influenza or Klebsiella infection, CNAPL maintained pathogen control without rekindling GVHD, decoupling inflammation control from infection susceptibility. This metabolism-centered, host-directed strategy restores immune-tissue homeostasis and provides a practical translational path for durable lung GVHD control with preserved antimicrobial defense.

Acute pneumonia triggered by pathogen infection and lung injury persists as a critical global life-threatening issue. Cluster of differentiation 24 (CD24), by selectively inhibiting the inflammatory response associated with damage-associated molecular patterns (DAMPs) through the interaction with Siglec, has appeared as a unique paradigm to alleviate acute pneumonia, yet its effective pulmonary delivery remains challenging. Here, we report on reactive oxygen species (ROS)–responsive and mucus-penetrable nanogels (ROSμNG) for pulmonary CD24 delivery to rescue acute pneumonia by selective inhibition of hyperinflammatory response. CD24-loaded nanogels (CD24-ROSμNG) exhibit excellent stability during nebulization, efficient mucus penetration, and inflammation-triggered CD24 release, affording over 80% drug enrichment in lung tissues through nebulization inhalation. In lipopolysaccharide-induced severe acute pneumonia mouse models, nebulized CD24-ROSμNG effectively attenuates cytokine storm, suppresses DAMP-mediated inflammation, and mitigates lung injury, achieving an over 3.5-fold increase in survival rate compared to intravenous administration of over 12-fold higher dose of free CD24. In an H1N1 virus influenza model, CD24-ROSμNG not only prevents cytokine storm but also preserves neutrophil-mediated viral clearance by limiting excessive neutrophil extracellular trap formation, thereby avoiding uncontrolled inflammation while maintaining antiviral defenses. These inhalable CD24 nanogels establish a strategy to manage pulmonary hyperinflammatory disorders.

Intra‐abdominal hemorrhage is a life‐threatening condition with high mortality. Rapid localization of the bleeding point is crucial. Conventional computed tomography (CT) imaging is limited by the rapid diffusion and poor retention of small‐molecule iodine agents, restricting sensitivity and imaging duration. To overcome these challenges, an “AB‐type” hydrogel CT contrast system is developed based on bio‐orthogonal click chemistry, designed to enhance both detection sensitivity and spatial precision. The system consists of iodized oil‐loaded liposomal nanoparticles (INb NPs) administered intravenously and tetrazine‐functionalized hyaluronic acid (HA‐Tz) delivered intraperitoneally. At the bleeding site, the two components undergo a rapid click reaction, forming an in situ hydrogel that anchors the contrast agent for prolonged retention and precise localization. This approach demonstrated efficient gelation in vitro and robust performance in vivo, significantly extending the imaging window and sensitivity compared with Iohexol. HA‐Tz@INb NPs enhance CT signal intensity and imaging duration by over 60 fold, enabling sensitive detection of occult bleeding. The hydrogel exhibits excellent biosafety, being removable by lavage and fully degradable within days without adverse effects. By integrating nanotechnology, click chemistry, and hydrogel engineering, this strategy provides a clinically translatable diagnostic platform with superior precision and sensitivity for intra‐abdominal bleeding.

Ultrasonic energy harvesting technologies have gained much attention for biomedical applications due to their several desirable features including low-energy attenuation and strong penetration capability. In this work, flexible piezoelectric poly(vinylidenefluoride-co-trifluoroethylene) (P(VDF–TrFE))/barium titanate (BaTiO₃, BT) membranes, capable of converting ultrasound energy to electric energy, were fabricated by an electrospinning process and their effects on the wound healing behaviors with/without ultrasonic stimulation were investigated. The piezoelectric membranes showed excellent electric outputs and can be used as a sustainable power source to quickly charge LEDs and capacitors. The penetration capability of ultrasound waves was investigated by implanting the membranes at different depths of porcine tissue. The membrane was able to generate a high voltage of 8.22 V even at a depth of 4.5 cm. Furthermore, ultrasonic stimulation on the piezoelectric membranes facilitated the proliferation and migration of the fibroblasts, and a cell migration rate of 92.6% was obtained after 24 h in the cell migration test. Under ultrasonic vibration, the electric field generated from the membranes accelerated the wound closure rate in an animal wound model. These results demonstrated the effectiveness of the flexible piezoelectric membranes in stimulating cellular behaviors, which may provide a new therapeutic strategy for wound care.

Antimicrobial resistant (AMR) infections are a growing threat to public health and there is a general lack of development in new antibiotics. Here, a dextran‐coated stimuli‐responsive nanoparticle (NP) that encapsulates the hydrophobic antibiotic, rifampicin, and specifically binds bacteria to overcome AMR infections is reported. The NP shows a strong affinity with a variety of pathogens in vitro and effectively accumulates in the bacterial infected tissues. The NP is activated by either low pH or high reactive oxygen species in the infectious microenvironment, and releases both cationic polymer and rifampicin that display synergistic activity against AMR pathogens. The NP carrier also enables the antibiotic to penetrate both bacterial biofilms and mammalian cells, thus allowing the elimination of biofilm and intracellular infections. The NP formulation demonstrates both safety and efficacy in two animal infection models against either Gram‐negative or Gram‐positive AMR pathogens.

An urgent need for developing new antimicrobial approaches has emerged due to the imminent threat of antimicrobial‐resistant (AMR) pathogens. Bacterial infection can induce a unique microenvironment with low pH, which can be employed to trigger drug release and activation. Here, a pH‐responsive polymer–drug conjugate (PDC) capable of combating severe infectious diseases and overcoming AMR is reported. The PDC is made of a unique biodegradable and biocompatible cationic polymer Hex‐Cys‐DET and streptomycin, a model antibiotic. The two components show strong antimicrobial synergy since the polymer can induce pores on the bacterial wall/membrane, thus significantly enhancing the transport of antibiotics into the bacteria and bypassing the efflux pump. The PDC is neutralized for enhanced biocompatibility under physiological conditions but becomes positively charged while releasing the antibiotic in infected tissues due to the low pH. Additionally, the polymer contains disulfide bonds in its main chain, which makes it biodegradable in mammalian cells and thus reducing the cytotoxicity. The PDC can effectively penetrate bacterial biofilms and be taken up by mammalian cells, thereby minimizing biofilm‐induced AMR and intracellular infections. The PDC exhibits remarkable antimicrobial activity in three in vivo infection models, demonstrating its broad‐spectrum antimicrobial capability and great potency in eliminating AMR infections.

A double-network nanogel, composed of a silane-cross-linked polyethylenimine (PEI) network (i.e., PEI-S) and a pH-responsive poly(2-(hexamethyleneimino) ethyl methacrylate) (PC7A) polymer, was developed for efficient DNA transfection. The chemical cross-linking and hydrophobic interactions in the two networks led to improved stability outside the cell and also pH-triggered intracellular release of DNA. The nanogel with an optimal PEI-S and PC7A weight ratio of 1.3:1 exhibited significantly higher transfection efficiency than Lipofectamine 2000 in multiple cell lines. The nanogel also possessed a small size with a hydrodynamic diameter of 55 nm, low cytotoxicity, and superior stability in serum-containing media. Moreover, besides the PEI-based gene delivery system, we have also demonstrated that addition of the PC7A polymer to several types of cationic polymers commonly used for gene delivery also led to significant transfection enhancement of the resulting nanoparticles, suggesting that the PC7A polymer may be a universal additive that can benefit versatile cationic polymer-based gene delivery systems.

Gene therapy holds great promise for various medical and biomedical applications. Nonviral gene delivery systems formed by cationic polymer and nucleic acids (e.g., polyplexes) have been extensively investigated for targeted gene therapy; however, their in vitro and in vivo stability is affected by both their intrinsic properties such as chemical compositions (e.g., polymer molecular weight and structure, and N/P ratio) and a number of environmental factors (e.g., shear stress during circulation in the bloodstream, interaction with the serum proteins, and physiological ionic strength). In this review, we surveyed the effects of a number of important intrinsic and environmental factors on the stability of polymeric gene delivery systems, and discussed various strategies to enhance the stability of polymeric gene delivery systems, thereby enabling efficient gene delivery into target cells. Future opportunities and challenges of polymeric nucleic acid delivery nanosystems were also briefly discussed.