Prostacyclin analogues are effective treatments in pulmonary arterial hypertension (PAH), especially in advanced stages. Treprostinil, a stable prostacyclin analogue, can be administered as subcutaneous and intravenous infusions, oral extended-release tablets and inhalation. Inhalation offers several advantages over other routes of administration, including direct access to the lungs for localized therapy, reduced infection risk, and a painless, convenient mode of delivery. However, small lipophilic molecules like treprostinil are absorbed into the bloodstream within minutes after inhalation, resulting in a short duration of action in the lungs and systemic side effects. To address these limitations, we developed a novel strategy involving a double treprostinil prodrug tailored for pulmonary delivery. The prodrug consists of treprostinil di-esterified at its carboxylic acid with a polyethylene glycol (PEG) chain, and at its C11 hydroxyl group with butyric acid. The prodrug exhibited sustained treprostinil release in bronchoalveolar lavage fluid and serum, supporting its suitability for pulmonary delivery. It was cleaved by initial hydrolysis of the PEG chain, followed by subsequent cleavage of the short-chain fatty acid. Ex vivo studies in isolated pulmonary artery rings showed a delayed and prolonged vasorelaxation effect of the conjugate compared to the free drug. In vivo studies demonstrated significant lung retention, with detectable quantities of the compound remaining in the lungs 24 h after administration, and a markedly reduced peak serum concentration following inhalation. This double-prodrug approach represents a promising strategy for improving PAH treatment by optimizing local, sustained treprostinil delivery while minimizing systemic exposure.

Chronic endometritis (CE) is an important factor contributing to infertility and adverse pregnancy outcomes. Current clinical management mainly relies on antibiotics such as ceftizoxime (CTX), whose efficacy is limited by poor oral bioavailability and short half-life. To address these limitations, this study developed an intelligent, responsive hydrogel incorporating Leonurus japonicus Houtt derived extracellular vesicles (EVs) loaded with CTX. The hydrogel forms sustained-release drug reservoir in situ within the uterine cavity, enabling controlled release in response to the local inflammatory microenvironment. EVs can effectively regulate the inflammatory microenvironment by inhibiting activation of NF-κB pathway and NLRP3 inflammasome, downregulating the pro-inflammatory factor TGF-α, and upregulating the anti-inflammatory factors IL-10 and TGF-β1, thereby significantly promoting endometrial repair and reducing fibrotic areas. Meanwhile, CTX provides targeted antibacterial activity to eliminate pathogens and control infection. Through exerting antibacterial, anti-inflammatory, and tissue repairing, the developed intelligent, responsive hydrogel system offers a promising strategy for treatment of CE.

As an important barrier tissue, the intestinal mucosa is responsible for regulating immunity, absorbing nutrients, and maintaining microbial homeostasis. Structural damage or functional impairment of the mucosa not only leads to a series of mucosa-related diseases but also may cause pathological changes in extramucosal organs. Given the central role of mucosal dysfunction in the onset and progression of various diseases, effectively regulating mucosal function and improving drug delivery efficiency are critical for improving clinical outcomes in gastroenterology. This article systematically reviews the structural characteristics and main functions of the intestinal mucosa, and analyzes the manifestations and underlying mechanisms of mucosal dysfunction. Based on this, we summarize recent advances in barrier enhancement, precise tissue and cell-level targeting, and microenvironment-responsive delivery strategies, and further elaborate on the latest progress in bio-inspired nanosystems for the treatment of gastrointestinal diseases. Finally, this article discusses the clinical trial progress, current challenges, and future development prospects of artificial intelligence optimization technology in the regulation of intestinal mucosa and drug delivery, aiming to provide theoretical basis and research references for in-depth studies on the regulation of intestinal mucosa function and the clinical application of related delivery systems.

Sterile inflammation driven by cell-free DNA (cfDNA) and reactive oxygen species (ROS) underlies acute inflammatory disorders, yet current therapies fail to specifically target these upstream mediators. We report a dynamic covalent/coordinated nanonetwork (DC[2] NNW) that combines drug delivery, DNase-mimetic and ROS-scavenging functions through reaction-induced self-assembly and cerium coordination. DC[2] NNWs efficiently degrade cfDNA, scavenge ROS, and release the loaded therapeutics, suppressing TLR9/NF-κB/NLRP3 and TLR4/MyD88/JAK signaling. In murine models of acute kidney injury (AKI) and endometritis, DC[2] NNWs selectively accumulated in inflamed tissues, restored organ function, alleviated injury, and reduced oxidative stress. Transcriptomic analysis further showed downregulation of pro-inflammatory and neutrophil extracellular trap (NET)-associated genes, alongside activation of metabolic repair pathways including fatty acid oxidation and mitochondrial respiration. This multifunctional nanozyme platform, with its drug delivery properties, offers a targeted and upstream approach for modulating innate immune activation and metabolic dysfunction in AKI, endometritis, and other sterile inflammatory diseases.

Bepotastine possesses a short half-life (~2 h) and a narrow absorption window limited to the upper small intestine, necessitating a gastro-retentive drug delivery system for once-daily administration. In this study, we developed a low-density gastro-retentive tablet designed for instantaneous floating (zero lag time) to prevent premature gastric emptying-a critical limitation of conventional floating systems. This was achieved through a rational engineering approach using AutoCAD-based geometric integration to precisely control the initial apparent density below 1.004 g/cm[3]. The synergistic combination of low viscosity hypromellose (15 cP) and magnesium aluminometasilicate facilitated immediate buoyancy and sustained it for over 4 h through wicking-induced air entrapment and robust gel layer formation. In beagle dogs, the gastro-retentive tablet achieved 95.7% systemic exposure relative to a twice-daily reference, whereas non-floating sustained-release formulations reached only 64.5-88.6%, highlighting the necessity of gastric retention. Notably, a randomized clinical study in 28 healthy subjects confirmed that the scaled-up gastro-retentive formulation was bioequivalent to the reference product. Produced via standard manufacturing processes, the 100,000-tablet batch also demonstrated no clinically significant food effect. Species-specific physiologically based pharmacokinetic modeling mechanistically estimated gastric residence times of approximately 180 min in beagles and 360 min in humans, supporting the interpretation that the system may withstand multiple interdigestive migrating motor complex cycles. These findings validate the proposed gastro-retentive platform as a clinically viable, industrially scalable strategy for drugs with site-specific absorption.

Respiratory diseases represent a severe global health burden. However, the clinical efficacy of conventional therapeutics is severely limited by complex pulmonary physiological barriers, including mucociliary clearance, alveolar-capillary barrier, and alveolar macrophage phagocytosis. Biomimetic nano drug delivery systems (Nano-DDS) have emerged as a transformative strategy to overcome these obstacles by simulating the structural and functional attributes of biological entities. This review systematically summarizes the design paradigms of lung-targeted Nano-DDS, categorizing them into compositional, morphological, functional, and comprehensive bionics. We critically examine component bionics, utilizing naturally derived viral nanoparticles, cells and extracellular vesicles for their intrinsic biocompatibility. Furthermore, we explore morphological bionics, detailing how mimicking the geometry of pathogens or cells optimizes pulmonary deposition and evades immune surveillance. We then highlight functional bionics, particularly cell membrane camouflage and ligand modification, which disguise synthetic nanoparticles as biological entities to enhance bio-interfacial compatibility and site-specific accumulation. Finally, we discuss the integration of these strategies into comprehensive and intelligent Nano-DDS for precision medicine. By elucidating these bio-inspired mechanisms, this work aims to provide a theoretical framework for overcoming current bottlenecks in pulmonary drug delivery, ultimately facilitating the translation of next-generation therapeutics from bench to bedside.

Immunosenescence increases susceptibility to varicella-zoster virus (VZV) infection in the elderly while compromising vaccine responsiveness. Although clinical adjuvants such as AS01 have improved vaccine efficacy, challenges associated with saponin-based components and separate antigen-adjuvant formulations persist. Here, we developed a nanovaccine, NP(gEIM), that co-encapsulates VZV glycoprotein E (gE) with the TLR4 agonist MPLA and TLR7/8 agonist IMQ in lipid nanoparticles via flash nanocomplexation (FNC), enabling coordinated co-delivery of antigen and adjuvants. NP(gEIM) efficiently targeted draining lymph nodes and promoted antigen-presenting cell uptake and maturation. In young and aged mice, NP(gEIM) elicited gE-specific antibody responses and Th1-biased cellular immunity comparable to AS01-adjuvanted gE vaccines while exceeding aluminum-adjuvanted vaccines. Moreover, NP(gEIM) enhanced IFN-γ and TNF-α production by antigen-specific CD4[+] and CD8[+] T cells while reducing immunosuppressive Treg and MDSC populations in aged mice. Notably, NP(gEIM) reshaped the TCR repertoire by promoting selective expansion of putative antigen-responsive T cell clones and altering TCR V/J gene usage and CDR3 length distribution, providing molecular insights into vaccine-induced T cell responses. Collectively, this study presents a nanovaccine strategy enabling coordinated delivery of antigen and dual TLR agonists. By integrating humoral and cellular immunity with TCR repertoire modulation, NP(gEIM) offers a potential strategy for improving vaccine responses in aging populations and developing vaccines against age-associated infectious diseases.

Acute lung injury arising from acute pancreatitis or sepsis remains a major clinical challenge and lacks specific therapeutic strategies. Neutrophil activation and infiltration, tightly governed by intracellular Ca[2+] signaling via ORAI1-based Ca[2+] release-activated Ca[2+] (CRAC) channels, play central roles in the pathogenesis of acute lung injury. Here, we engineered a neutrophil-targeted lipid nanoparticle (neutLNP) encapsulating the selective CRAC channel inhibitor CM4620 (Anti-Ly6G@CM4620-LNP) for intranasal delivery. The neutLNP efficiently suppressed neutrophil chemotaxis and reactive oxygen species production, and significantly attenuated lung injury in both pancreatitis- and sepsis-associated lung injury models. Compared with intranasally administered free CM4620, neutLNP produced greater reductions in selected histological and inflammatory endpoints. Pulmonary imaging and flow cytometry demonstrated distribution within the inflamed lung parenchyma and preferential association with pulmonary neutrophils, whereas pharmacokinetic analysis showed markedly lower plasma CM4620 exposure after intranasal than after intraperitoneal administration. Mechanistically, integrated transcriptomic and single-cell proteomic profiling of pulmonary neutrophils from neutrophil-specific Orai1-deficient mice identified CD166 as a downstream mediator of ORAI1 signaling. Further analyses showed that ORAI1 signaling transcriptionally promotes CD166 expression, at least in part through NFATc2. Together, these findings support intranasal neutLNP delivery as a locally directed strategy that enhances lung protection relative to intranasal free CM4620 while limiting systemic exposure compared with intraperitoneal delivery, and establish CD166 as a functionally important downstream mediator of ORAI1-dependent neutrophil adhesion in acute inflammatory lung injury.

Precise mitochondrial targeting in chondrocytes is essential for interrupting the vicious cycle of oxidative stress and cartilage degeneration in osteoarthritis (OA). Here, we develop a biomimetic nanoplatform (CM@SS31-Se) with dual targeting capability. This system comprises selenium nanoparticles with glutathione peroxidase mimetic activity as the antioxidant core, SS31 peptide for mitochondrial homing, and chondrocyte membrane coating for homotypic recognition. Following intra-articular injection, the nanoplatform demonstrates prolonged joint retention up to 14 days with favorable biocompatibility. Functionally, the outer membrane shell facilitates chondrocyte internalization through homotypic recognition, the SS31 peptide promotes mitochondrial accumulation through its cardiolipin binding affinity, and the selenium core subsequently provides sustained mtROS scavenging. These dual-targeting properties restore mitochondrial membrane potential and ATP synthesis, upregulate anabolic markers (SOX9, Col II, Aggrecan), and downregulate MMP13 and pro-inflammatory mediators, ultimately promoting the restoration of a regenerative phenotype in degenerative chondrocytes. Thus, this biomimetic nanoplatform enables guided mitochondrial functional restoration, demonstrating therapeutic potential for attenuating OA progression.

Although STING agonists have shown potential in reversing the "cold" tumor microenvironment (TME) by activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, their efficacy as monotherapy remains limited, and combination therapies face challenges such as poor synergy, suboptimal timing, and safety concerns. Nanocarriers have evolved from passive drug delivery vehicles into active immunomodulatory platforms, providing critical support for precision combination therapy through co-loading of multiple agents, spatiotemporally coordinated release, and cell-specific targeting. This review delineates STING-centered combination immunotherapy through rational nanocarrier engineering, from physicochemical tuning to programmable delivery. We catalogue nanoplatforms for multi-agent co-encapsulation, examine surface targeting and temporal modulation. Finally, we analyze clinical translational barriers and advance solutions, hoping to offer insights into the clinical translation of nanocarrier-based STING-targeted combination immunotherapy.

Biomimetic nanomedicine utilizing cell membrane cloaking has emerged as a promising approach to enhance nanocarrier performance by integrating the physicochemical benefits of synthetic nanoparticles with the biological functionalities of source cells. Nonetheless, single-source membrane systems are inherently limited by their restricted functionality, which constrains their capacity to address the complex pathological barriers present in various diseases. To address these limitations, hybrid membrane vesicles (HMVs) have been developed. These vesicles are formed by the fusion of two or more distinct membrane types and are engineered biomimetic platforms designed to integrate selected membrane-derived functions within a unified nanoscale architecture. By integrating membrane-derived functions, HMVs provide a modular framework for combining biological recognition with engineered cargo delivery. However, whether these functions are complementary or genuinely synergistic depends on the membrane architecture and the controls used for validation. Unlike previous reviews that mainly focus on single-source membrane-coated nanoparticles, extracellular vesicles (EVs), or general biomimetic nanomedicine, this Review defines HMVs as a distinct programmable biointerface platform and provides a membrane-combination-centered framework for understanding their design principles, functional complementarity, and translational challenges. Therefore, in this review, we systematically summarize the engineering strategies for constructing HMVs and propose a classification framework based on membrane origin. We focus on cancer-oriented HMVs and discuss how different membrane combinations can be rationally engineered to improve multimodal antitumor therapy. Although HMVs also show potential in other diseases, these non-cancer applications are discussed only as supportive examples to illustrate generalizable design principles. We further analyze how particular membrane combinations create functional complementarity to enhance efficacy through coordinated targeting and immune activation. Finally, we examine the significant challenges impeding clinical translation. Overall, current evidence supports HMVs as flexible preclinical platforms for integrating membrane-derived recognition with engineered drug delivery functions. However, their clinical translation will require more rigorous validation of membrane architecture, GMP-compatible manufacturing, bacterial membrane-associated immunogenicity, regulatory classification, pharmacokinetics, metabolic fate, and long-term safety.

KRAS is a prevalent oncogenic driver whose therapeutic targeting has remained challenging beyond the G12C mutation. Here, we developed a gene circuit platform that enables the in vivo self-assembly of small extracellular vesicles (sEVs) encapsulating KRAS-specific siRNAs for broad targeting of KRAS mutants. The system is based on intravenous injection of a synthetic gene circuit engineered to co-express KRAS-targeting siRNAs (directed against conserved regions or specific mutations such as G12D) and the colorectal cancer (CRC)-targeting peptide TCP-1 in hepatocytes. Upon hepatic absorption, the circuit drives the production of sEVs that package the siRNAs and display TCP-1 on sEV surface for tumor-specific delivery. In orthotopic models of KRAS[G12D]-, KRAS[G12V]-, and KRAS[G13D]-driven CRC, the platform mediated efficient tumor targeting and significantly suppressed tumor growth, achieving complete regression in some cases. Tandem circuits co-expressing two siRNAs exhibited synergistic and superior efficacy compared to single-siRNA circuits or the small-molecule inhibitor MRTX1133. Mechanistic studies confirmed downregulation of KRAS expression and suppression of downstream ERK and AKT phosphorylation. Comprehensive safety evaluation revealed minimal off-target effects and no detectable systemic toxicity, highlighting the favorable safety profile of the platform. Collectively, this study establishes a robust and targeted siRNA delivery system that effectively overcomes the historical limitations of KRAS targeting, providing a promising therapeutic strategy for a broad spectrum of KRAS-driven cancers.

Hydrogels are widely used as an effective platform for therapeutic drug delivery, wound healing and corrective vision, among other applications. Their tunability and adaptability, including the choice of natural or synthetic polymers, allow the design of hard or soft hydrogels with variable loading capacity, viscosity, and adhesiveness, tailored for diverse physiological organs and tissues. Common targeted sites include the eye, skin, and joints, whereas the peritoneal cavity remains comparatively less explored. Designing hydrogels for the eye versus the peritoneal cavity share similar challenges, such as biocompatibility, sterility, and injectability, but also distinct challenges, such as transparency, swelling percentage and volume. Although the eye and the peritoneal cavity differ markedly in their anatomy and physiology, both provide suitable environments for hydrogel application, offering an opportunity to identify design principles that extend beyond organ-specific contexts. In this review, we examine how the physiological characteristics of the eye and the peritoneal cavity influence hydrogel formulation and performance. By comparing these two contrasting environments, we also explore whether design strategies developed in one field may be relevant to the other. Finally, we discuss whether a single hydrogel design can realistically meet the requirements for applicability both in the eye and the peritoneal cavity.

Myocardial infarction (MI) remains a major challenge in clinical practice, as the irreversible loss of cardiomyocytes and the limited repair capacity of the adult heart constrain cardiac repair. Traditional cell therapy once held great promise, but its clinical application has been constrained by issues such as low cell survival, immune rejection and procedural complexity. Against this background, extracellular vesicles (EVs) have attracted attention as a paracrine delivery strategy. By delivering bioactive cargo, including proteins, nucleic acids and lipids, EVs mediate intercellular communication and thereby support cardiac repair. This review focuses on the clinical potential of EVs, comparing the advantages, limitations and safety risks of EVs from different cellular origins, and places particular emphasis on engineered delivery strategies aimed at improving targeting, retention and therapeutic efficacy. In parallel, we examine the core barriers to clinical translation, including large scale manufacturing challenges, batch to batch consistency, storage stability, and regulatory and ethical issues; it is these barriers, rather than insufficient efficacy, that constitute the key bottleneck to the clinical application of EVs. Compared with existing reviews, this review, by emphasizing a clinical translation perspective, systematically analyzes the key issues facing EV-based therapeutic strategies in their progression from experimental research to clinical application, providing a practical theoretical framework for EV-based myocardial repair therapies and clarifying the prospects for EVs in the treatment of MI.

Central nervous system (CNS) diseases remain a therapeutic challenge due to the blood-brain barrier (BBB). The nose-to-brain pathway offers a promising non-invasive route to bypass the BBB, yet the impact of nanocarrier size on this multi-stage delivery process is poorly understood. This study systematically investigated the role of particle size using solid lipid nanoparticles (SLNS) of 80, 120, 240, 360, and 480 nm, formulated into nasal sprays. In vivo imaging in mice revealed a non-monotonic relationship, with 240 nm SLNS (SLNS3) achieving peak brain accumulation via both olfactory and trigeminal pathways, approximately 1.7-fold higher than other sizes. In vitro models deconstructing the delivery cascade showed that while smaller particles (80 nm) penetrated mucus and nasal epithelium more efficiently, the 240 nm SLNS exhibited superior uptake by neuronal cells and unparalleled transcytosis efficiency to microglia and glioma cells. Mechanistic studies unveiled that SLNS3 uniquely exploited multiple endocytic pathways (clathrin, caveolae, and macropinocytosis) for entry and was preferentially trafficked to the endoplasmic reticulum and Golgi apparatus, facilitating transcellular transport. The superior nose-to-brain delivery efficiency of 240 nm SLNS3 was also validated by a glioma model. Together, our findings pinpoint 240 nm as an optimal size within the SLNS system, reveal the governing cellular mechanisms, and provide a valuable reference for the rational design of nose-to-brain nanomedicines.