Drug-resistant bacterial infections increasingly evade available antimicrobials, and many existing antimicrobial peptides remain limited by instability, toxicity to mammalian membranes and high manufacturing cost. Here we introduce a modular peptide technology that self-assembles into nanofibres on bacterial surfaces through a membrane-anchoring biphenyl group, a diphenylalanine linker and a cationic minimalistic peptide that together enable selective disruption of drug-resistant pathogens. Using cryogenic electron microscopy, molecular dynamics simulations, lipid-nanoparticle membrane mimetics and binding thermodynamics, we show that the peptide first forms short nanofibres that dock onto phosphatidylglycerol and then elongates into nanofibres that penetrate and destabilize the bacterial membrane without inducing resistance. The nanofibres retain antibacterial activity when recycled from killed bacteria and outperform vancomycin and several classical antimicrobial peptides against dense bacterial populations in vitro. In a mouse model of methicillin-resistant Staphylococcus aureus pneumonia, inhaled peptide nanofibres eradicate pulmonary infection and restore lung architecture without detectable toxicity. This modular strategy enables the design of potent, selective and low-cost antimicrobials.

Atherosclerotic macrophages predominantly exhibit a pro-inflammatory phenotype, driving chronic inflammatory and accelerating atherosclerotic progression. Interferon regulatory factor 5 (IRF5) is highly expressed in lesional macrophages within advanced atherosclerotic plaques, where it promotes the secretion of pro-inflammatory cytokines. However, current approaches lack an effective therapeutic strategy to specifically silence this gene in lesional macrophages for atherosclerosis treatment. This study aims to develop and evaluate a dual-targeted, siRNA-based nanotherapeutic platform that selectively acts on atherosclerosis-promoting genes in plaque macrophages, offering a potential strategy for treating atherosclerosis by reprogramming lesional macrophages. Here we designed and developed dual-targeted liposome-based nano-immunotherapeutics encapsulating small interfering RNA (siRNA) against IRF5 (siIRF5) to reprogram macrophage phenotypes within advanced plaques. In high-fat diet-fed ApoE -/- mice with advanced atherosclerotic plaques, dual-targeted siIRF5-loaded liposomes effectively accumulate within lesional macrophages, downregulate IRF5 expression, and promote anti-inflammatory macrophage polarization. Moreover, this siIRF5-based nanoimmunotherapy significantly reduces plaque burden and enhances plaque stability in two independent murine models of atherosclerosis. Furthermore, this siIRF5 nanoimmunotherapy exhibits biocompatibility even after long-term administration, underscoring its translational potential for clinical application in atherosclerosis treatment. This study introduces an innovative dual-targeted siRNA-based nanotherapeutic strategy that acts on atherosclerosis-promoting genes in plaque macrophages, offering a promising therapeutic avenue for atherosclerosis and other macrophage-driven inflammatory diseases.

Macrophages within advanced atherosclerotic lesions typically exhibit impaired efferocytosis and tend to adopt a pro-inflammatory M1-like phenotype, leading to the progression of atherosclerosis. Despite this challenge, the development of biocompatible nanotherapeutics capable of effectively remodeling macrophage efferocytosis and phenotype remains elusive. Here, we developed engineered targeted-peptide-modified nanocarriers (PP) and demonstrated their potential to restore macrophage efferocytosis while promoting re-polarization towards an anti-inflammatory M2-like phenotype. Furthermore, PP efficiently facilitated the delivery of an inflammation-resolving-drug to lesional macrophages within advanced atherosclerotic lesions. This combination approach substantially enhanced the anti-atherosclerotic efficacy of PP-based nanomedicine, effectively ameliorating atherosclerosis progression. In advanced plaque-bearing ApoE−/− mice, PP nanomedcine efficiently accumulated in atherosclerotic plaques, notably restoring macrophage efferocytosis, promoting anti-inflammatory M2-like macrophage polarization, and leading to reduced plaque areas and enhanced plaque stability. This study not only underscores the new pleiotropic effects of PP to restore macrophage efferocytosis and modulate macrophage phenotype, but also highlights the promising potential of PP for the treatment of atherosclerosis and diseases associated with macrophage dysfunction.

Despite four decades of effort, neither a cure nor a preventive vaccine exists for HIV-1. HIV-1 vaccine development faces persistent barriers, including the rapid mutation rate of the virus, its genetic diversity, immune evasion strategies and the establishment of latent reservoirs. Although antiretroviral therapies effectively suppress replication, limitations such as lifelong adherence, drug resistance and inability to eliminate reservoirs underscore the need for novel vaccines. Critically, the foremost challenge in HIV-1 vaccines remains the induction of broadly neutralizing antibodies — a hurdle rooted in the virus’s structural complexity and host immune tolerance. mRNA technology offers rapid scalability, favourable safety profiles (avoiding viral vector-associated risks) and the capacity to elicit potent immune responses, possibly positioning mRNA-based medicine as a potential solution to the challenges posed by HIV-1. Additionally, mRNA enables swift iteration of immunogen designs, potentially accelerating broadly neutralizing antibody-focused strategies. Preclinical studies and early-phase clinical trials are actively exploring mRNA technology to overcome obstacles in HIV-1 immunization. In this Review, we explore mRNA technology, evaluate clinical trials of HIV-1 mRNA medicine and discuss persistent challenges in the development of mRNA-based interventions against HIV-1. mRNA technologies offer potential solutions for HIV-1 vaccine development by enabling rapid, safe and modular antigen design that can initiate rare antibody lineages required for broad protection. In this Review, we discuss preclinical and early clinical evidence, outline remaining challenges — particularly breadth and durability — and discuss delivery and manufacturing advances that may help translate these approaches into effective preventive and therapeutic strategies.

Bacterial biofilms, prevalent in human infections, present a major barrier to effective antibacterial therapy due to limited drug permeability and resistance. Here we introduce a ‘trick-bacteria-with-bacteria’ strategy that employs bacteria modified via calcium chloride treatment and antibiotic loading, followed by ultraviolet inactivation. These modified bacteria integrate selectively into biofilms of the same species, enabling targeted intra-biofilm drug release triggered by local pH and hydrogen peroxide. Species-specific integration is essential, as mismatched strains exhibit spatial segregation due to differences in surface adhesins and protein profiles. The strategy is effective against polymicrobial biofilms and demonstrated efficacy in treating biofilms formed by Staphylococcus aureus, Escherichia coli and Candida albicans. It also reinvigorates biofilm-associated macrophages by inducing the release of biofilm-derived l-arginine, enhancing immune responses. In vivo studies using subcutaneous and bone implant infection models showed stronger biofilm eradication and longer-term immunity in animals treated with modified bacteria compared with those treated with antibiotics, including resistance to re-infection. This approach could be adapted to modify infection-related bacteria from patients for personalized intra-biofilm drug delivery. Chemically modified and permeabilized bacteria allow for antibiotic delivery inside biofilms, inducing long-term immune protection and eradicating implant-related infections in preclinical models.

Cardiovascular disease (CVD) remains the leading cause of global mortality, prompting urgent efforts to explore novel therapeutic approaches. The remarkable success of mRNA technology brings new possibilities for CVD treatment, with numerous preclinical studies establishing proof-of-concept, and several have advanced into clinical trials. Leveraging cumulative experience in mRNA therapeutics, improved understanding of cardiovascular pathophysiology and developments in nanotechnology, genome editing and RNA synthetic biology, mRNA medicine presents promising opportunities for addressing CVDs. Here, we provide an overview of the advancements of mRNA-based biotechnologies for CVDs, including mRNA modifications, mRNA delivery platforms, mRNA-encoded genomic and epigenomic editing, and mRNA-based chimeric antigen receptors for immune cell engineering. We also summarize preclinical and clinical applications of mRNA medicine in various CVDs, including hypercholesterolemia, atherosclerosis, ischemic cardiac injury, cardiac fibrosis and cardiac amyloidosis. Finally, we discuss the challenges and highlight the future directions for bench-to-bedside translation of mRNA technology in the field of CVDs.

Daily subcutaneous injections of recombinant interleukin-10 (IL-10) demonstrated encouraging but preliminary efficacy in certain tumour types during early phase clinical trials. However, these antitumour effects were not consistently replicated in larger trials, probably due to insufficient intratumoural recombinant IL-10 accumulation, which ultimately restricted clinical benefit. Here we show that intravenous injections of IL-10 messenger RNA (mRNA) nanoparticles (IL-10-mRNA@NPs) induce potent immune surveillance across diverse preclinical tumour models and mitigate systemic toxicities. In particular, IL-10-mRNA@NPs sustain in situ IL-10 production within tumours, promoting substantial infiltration and proliferation of cytotoxic T cells, activation and maturation of dendritic cells, and an augmented expression of major histocompatibility complex class I molecules in immunosuppressive orthotopic early stage hepatocellular carcinoma tumours. Moreover, in mice with orthotopic middle-to-late-stage hepatocellular carcinoma tumours, combining IL-10-mRNA@NPs with immune checkpoint blockades results in 43% of mice showing complete tumour eradication and a sixfold increase in median survival compared with mice treated with immune checkpoint blockades alone. Furthermore, this combination induces long-lasting antitumour immune memory, conferring 100% protection against tumour rechallenges. The intravenous IL-10-mRNA@NPs strategy may have potential to overcome the challenges associated with recombinant IL-10 in clinical trials across a broad spectrum of immunosuppressive tumours.

Regenerative medicine presents a transformative approach to repairing or replacing damaged tissues and organs. While traditional gene therapies hold relatively long-lasting expression, concerns such as genomic integration risks, high costs, and regulatory complexities have limited their clinical application. The success of messenger RNA (mRNA) vaccines has introduced mRNA technology as a promising therapeutic platform, providing a potentially safe and translatable intervention for regenerative medicine. In this review, we provide deep insights into the advances in regenerative therapies with a focus on rationally designed mRNA techniques. We highlight mRNA-mediated strategies, including protein supplementation, cell reprogramming, and cell transdifferentiation, which enable precise control over cell fate. These modalities, driven by innovations in mRNA synthesis, chemical modifications, and nano-delivery platforms, mobilize cells by redirecting their differentiation toward specific types. Finally, we propose an integrated overview of preclinical and clinical progress, addressing challenges and the transformative potential of mRNA technology for clinical translation in engineered regenerative medicine.

BACKGROUND:Impaired efferocytosis of macrophages within advanced atherosclerotic plaques leads to plaque deposition and rupture, ultimately resulting in atherothrombotic events. Effective restoration of efferocytic capacity in lesional macrophages remains a challenge in atherosclerosis treatment. METHODS:We developed an engineered small interfering RNA (siRNA) nanoparticle platform that can therapeutically manipulate lesional macrophages by inhibiting an overexpressed plaque-destabilizing macrophage molecule: IRF5. RESULTS:IRF5 siRNA (siIRF5) nanoimmunotherapeutics were efficiently taken up by lesional macrophages, particularly Cd11c+ and Trem2hi macrophages, and enhanced their phagocytic clearance of apoptotic cells by efficiently silencing IRF5 expression within these macrophage subsets in atherosclerotic plaques. This resulted in remarkable therapeutic efficacy, as evidenced by reduction of necrotic core area and enhancement of plaque stability in 2 independent ApoE-/- murine models of atherosclerosis. Single-cell RNA sequencing analysis revealed that siIRF5 nanoimmunotherapeutics increased the proefferocytic receptors while decreasing the expression of proinflammatory genes associated with cytokine and chemokine pathways in lesional macrophages. CONCLUSIONS:These findings highlight the potential of siRNA nanoimmunotherapeutics for treating atherosclerosis and other diseases resulting from impaired efferocytosis in macrophages.

Liquid crystal elastomers (LCEs) are anisotropic, viscoelastic materials integrating polymer networks and liquid crystals. While their mechanical responses have been extensively studied, their fracture behavior remains largely unexplored. Specifically, the effect of the deformation-director coupling on LCE fracture paths is unknown, and fracture criteria for LCEs are not yet established. To address this gap, we combine experimental and theoretical approaches to investigate fracture propagation in LCEs. We stretch edge-cracked monodomain LCE samples, recording their stress-stretch responses and crack paths under varying initial directors and stretching rates. Our findings reveal that cracks can change direction during propagation, which are highly dependent on both the initial director and the stretching rate. To further understand LCE fracture behavior, we develop a rate-dependent phase-field fracture model, which is validated through experiments, and demonstrates the ability to predict complex fracture paths. Our study paves the way for designing LCEs with enhanced fracture properties, imperative for their future applications.

Hydrogels have emerged as versatile therapeutic platforms with immense potential for treating various diseases, due to their tunable properties and biocompatibility. Recent innovations, including injectable, self-assembling, and bioadhesive hydrogels, have broadened their biomedical applications, driven by advancements in materials chemistry. This review systematically examines the role of chemical principles in designing and customizing therapeutic hydrogels, with a focus on hydrogelation mechanisms, swelling ratios, mechanical properties, and biological interactions. By highlighting key studies in this field, this review explores how chemical chain modifications, cross-linking strategies, and cargo delivery systems have been tailored to achieve diverse functions, such as drug depots, wound dressings, antiadhesive barriers, and regenerative scaffolds. Addressing the gap in comprehensive analyses, this review underscores the integration of chemical design principles to optimize hydrogel properties for targeted therapies and discusses future opportunities to advance therapeutic hydrogel technology for a wide range of biomedical applications.

Nanoparticle-based drug delivery systems hold promise for tumor therapy; however, they frequently encounter challenges such as low delivery efficiency and suboptimal efficacy. Engineered living cells can redirect drug delivery systems to effectively reach targeted sites. Here, we used living macrophages as vehicles, attaching them with GeS nanosheets (GeSNSs) carrying β-elemene for transport to tumor sites. GeSNSs act as efficient sonosensitizers, enhancing ultrasound-induced reactive oxygen species generation for treating 4T1 breast tumors. Notably, macrophage hitchhiking delivery of β-elemene–loaded GeSNSs not only achieves high accumulation in tumor regions and suppresses tumor growth under ultrasound treatment, but also effectively remodels the immunosuppressive tumor microenvironment by improving M1-like macrophage polarization and enhancing the populations of mature dendritic cells, CD4 + , and CD8 + lymphocytes, thereby facilitating enhanced sonodynamic chemoimmunotherapy. These findings underscore the potential of macrophage hitchhiking strategy for drug delivery and suggest broader applicability of engineered living materials–mediated delivery technologies in disease therapy.

PROteolysis TArgeting Chimeras (PROTACs), as a promising therapeutic modality, have been exploited to degrade specific pathogenic proteins. However, the in vivo antitumor efficacy of PROTACs is seriously impaired by its poor pharmacokinetics and insufficient tumor distribution, consequently restricting their clinical applications. Herein, we report a pH/enzyme cascade-responsive nano-PROTACs (CRNPs) by integrating the cathepsin B-cleavable Gly-Phe-Leu-Gly (GFLG) linked PROTAC onto ultra-pH-sensitive (UPS) nanoplatform for enhanced tumor-specific ALK degradation and precise cancer therapy. The CRNPs exhibit a stable nanostructure with a diameter of 33 nm under physiological conditions, while rapidly dissociate at pH 6.0 and are subsequently cleaved by cathepsins B to effectively release the PROTAC payload. This further results in efficient ALK degradation, p-ALK reduction, G0/G1 phase cell cycle arrest, and suppression of tumor cells proliferation. Moreover, the cascade-responsive design dramatically improves the in vivo pharmacokinetics via prolonged circulation lifetime as well as enhanced tumor specific accumulation and release of PROTAC. Consequently, CRNPs significantly augment the antitumor efficacy, achieving with over 94 % suppression in Karpas299 tumor models, while demonstrating good biocompatibility in vivo. These findings highlight the potential of cascade-responsive nanocarriers for delivering PROTACs to combat a wide range of cancers by attacking their pathogenic proteins.

Molecular hydrogen (H2) protects organs from reactive oxygen species damage associated with ischemia–reperfusion (I/R) injury. Existing H2 delivery methods, such as gas inhalation and H2-rich water consumption, target the entire body and experience leakage during administration. Here we engineer a portable hydrogel electrochemical cell that enables on-demand H2 production via the hydrogen evolution reaction. The system enables H2 controlled generation, localized storage and sustained diffusion to the tissue–device interface, with better controllability and sustainability. We conduct a thorough study of H2 evolution and dynamics in the hydrogel system, evaluating the influence of hydrogel polymer composition on the hydrogen evolution reaction kinetics, bubble morphologies and storage. We validate its protective effects (1) in vitro with cardiomyocytes and keratinocytes, (2) ex vivo in I/R hearts and (3) in vivo in skin I/R pressure ulcers. These findings demonstrate the potential of the hydrogel electrochemical cell design for efficient and sustainable H2 delivery in I/R therapy, which could be broadly applied in other gas-based therapies and drug delivery research. A wearable hydrogel-based electrochemical platform is presented for on-demand hydrogen gas therapy, enabling localized gas generation, storage and sustained delivery. This device offers a therapeutic modality for treating ischemia–reperfusion heart disease and skin bedsores, expanding bioelectronics applications in gas-phase chemical delivery.

Postsurgical tumor recurrence remains a major challenge, primarily driven by the resurgence of residual microtumors at surgical margins. The tumor microenvironment (TME) in these regions plays a decisive role in treatment outcomes. Here, we present an in situ sprayed fibrin hydrogel system that integrates chemically engineered homologous dying cancer cells (DCCs) as a sustained antigen reservoir with the anticancer agent β-elemene (ELE) to enhance anti-tumor immune responses and suppress local tumor recurrence. This immunotherapeutic hydrogel (DCCs@ELE@Gel) modulates the TME by promoting a favorable M1/M2 tumor-associated macrophage balance, facilitating dendritic cell maturation, and enhancing the cross-priming of cytotoxic T cells, collectively preventing tumor regrowth. Additionally, comprehensive proteomic analysis reveals key mechanisms linking the chemo-immunotherapeutic hydrogel to tumor recurrence suppression. Our findings introduce an approach that leverages engineered tumor cells within a hydrogel matrix for improved cancer immunotherapy, offering a versatile strategy for postsurgical tumor management.

The adrenal glands are essential endocrine organs that secrete key hormones maintaining physiological homeostasis. Herein, we established expandable three-dimensional (3D) human adrenocortical organoid (ACO) cultures that preserved the characteristic of zona fasciculata cell lineages and retained their capacity to produce cortisol. The ACOs could secrete glucocorticoids in response to physiological stimuli and thus rescue adrenalectomized mice, indicating their potential for the treatment of primary adrenal insufficiency. Furthermore, by introducing a hotspot pathogenic variant (PRKACA L206R) identified in Cushing's syndrome, we achieved the organoid disease modeling of cortisol-producing adenomas. In summary, this study establishes a human organoid platform to explore homeostasis and dysfunction in adrenal glands, suggesting future applications in disease modeling and regenerative medicine.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal (GI) tract with increasing global prevalence. Despite advancements in IBD management, current therapies suffer from limitations, such as premature drug degradation, insufficient retention at inflamed sites, and systemic off-target effects, resulting in suboptimal efficacy and increased adverse events. To address these challenges, this review presents a new paradigm for precision drug delivery in IBD, highlighting three critical strategies: (1) effective transfer—ensuring efficient drug transport to the intestinal region by overcoming complex GI physiological barriers; (2) enhanced retention—prolonging drug residence at inflamed lesions to maximize local therapeutic effects; and (3) pathology-targeting treatment—executing therapeutic interventions based on IBD-associated pathological features to achieve localized treatment and minimize systemic toxicity. We emphasize the integration of advanced biomaterials and engineered therapeutic platforms as enablers of these strategies and illustrate their interactions with IBD pathophysiology. By analyzing recent breakthroughs in drug delivery systems and bioresponsive materials, this review outlines the design principles and translational potential of next-generation IBD therapeutics, offering insights for the development of more effective and patient-centric treatment approaches.

Stretchable electronics capable of conforming to nonplanar and dynamic human body surfaces are central for creating implantable and on-skin devices for high-fidelity monitoring of diverse physiological signals. While various strategies have been developed to produce stretchable devices, the signals collected from such devices are often highly sensitive to local strain, resulting in inevitable convolution with surface strain-induced motion artifacts that are difficult to distinguish from intrinsic physiological signals. Here all-printed super stretchable strain-insensitive bioelectronics using a unique universal gradient interface (UGI) are reported to bridge the gap between soft biomaterials and stiff electronic materials. Leveraging a versatile aerosol-based multi-materials printing technique that allows precise spatial control over the local stiffnesses with submicron resolution, the UGI enables strain-insensitive electronic devices with negligible resistivity changes under a 180% uniaxial stretch ratio. Various stretchable devices are directly printed on the UGI for on-skin health monitoring with high signal quality and near-perfect immunity to motion artifacts, including semiconductor-based photodetectors for sensing blood oxygen saturation levels and metal-based temperature sensors. The concept in this work will significantly simplify the fabrication and accelerate the development of a broad range of wearable and implantable bioelectronics for real-time health monitoring and personalized therapeutics.