Background: Heart failure (HF) has a complex pathogenesis involving oxidative stress, inflammation, and energy metabolism disorders, and requires multi-target agents. Berberis kaschgarica Rupr. (BKR) is used in Uyghur folk medicine to improve cardiovascular health, but its cardioprotective mechanisms against HF remain unclear. Methods: UPLC-MS/MS was used to identify BKRE components; DPPH/ABTS assays evaluated antioxidant activity. The MTC of BKRE was determined in zebrafish, and its effects on ISO-induced HF zebrafish were assessed via cardiac function, apoptosis, oxidative stress, and inflammation indicators. Network pharmacology, molecular docking, transcriptomics, and qRT-PCR clarified targets and pathways. Results: BKRE contained 14 bioactive flavonoids/alkaloids with favorable drug-likeness, showing concentration-dependent DPPH and ABTS scavenging. In HF zebrafish, BKRE (5/10/20 μg/mL) dose-dependently improved cardiac function, inhibited apoptosis, reduced ROS and TNF-α/IL-6, restored GSH/T-SOD, activated the AMPK-PPARα-PGC-1α pathway by binding ALOX5/NQO1, etc. Conclusions: BKRE exerts multi-mechanistic cardioprotective effects, validating BKR’s ethnopharmacological value and highlighting it as a promising HF agent/functional food.

Plant-derived extracellular vesicles (PDEVs) are a novel category of natural nanocarriers with widespread availability, low immunogenicity, high biocompatibility, and inherent pharmacological activity. These features underscore their value as dual-function systems capable of serving as both carriers and bioactive agents. Unlike previous reviews that focused primarily on disease-specific applications or on individual engineering techniques, this review established a conceptual framework integrating three interconnected dimensions: (i) engineering strategies that address the inherent limitations of PDEVs (targeting, stability, loading efficiency); (ii) the carrier-performance-synergy paradigm linking PDEV composition to therapeutic outcomes; and (iii) gel-composite design principles that transform local retention into a controllable delivery platform. This review delves into various engineering methodologies, including targeted modification, enhanced stability, and optimized drug loading, while elucidating the performance characteristics of PDEVs as drug carriers, focusing on their protective, targeting, and controlled-release properties. It notably investigates the synergistic interactions between the intrinsic bioactivity of PDEVs and the drugs they deliver. Furthermore, this review highlights advanced applications of PDEV gel composites in localized drug delivery, specifically emphasizing their clinical potential for treating dermatological conditions. Finally, it highlights the current challenges faced by PDEVs and anticipates future research directions, such as synthetic biology, multi-omics analysis, and clinical translation. This review provides a theoretical framework for the rational design and clinical translation of PDEVs. It thereby promotes their innovative development in precision nanomedicine.

Plant-derived extracellular vesicles (PDEVs) have emerged as promising natural nanocarriers for biomedical applications owing to their distinctive ability to facilitate intercellular communication and transport bioactive molecules. In this review, we employ bibliometric analysis to identify research hotspots and trends, providing a comprehensive overview of these core themes. The bibliometric results reveal a sustained increase in annual publications in this field, with keyword analysis identifying drug delivery, cross-kingdom regulation, immunomodulation, engineering modification, and gut microbiota as five major research themes. The focus of research has evolved from early basic biological characteristics into engineered smart delivery platforms, with the application areas expanding from intestinal inflammation to neurological, metabolic, dermatological, and oncological diseases. This review systematically examines the core directions in this field. It compares the strengths and limitations of mainstream isolation methods and highlights the value of multi-omics integration, covering the molecular mechanisms of ferroptosis and gut microbiota regulation by PDEVs along with engineering strategies such as drug loading, surface modification, and membrane fusion. It also discusses the latest progress in frontier therapeutic applications of PDEVs, including cancer, inflammatory diseases, tissue regeneration and aesthetics, and neurological disorders. Finally, this review summarizes the key challenges confronting the field, including the lack of standardized protocols, production bottlenecks, and engineering obstacles. It also delineates future directions, including establishing international standardization definitions, advancing multi-omics and AI-driven mechanistic elucidation, developing scalable and efficient purification technologies, and executing systematic preclinical safety and pharmacokinetic evaluations to facilitate clinical translation.

The increasing consumption of polyphenol-enriched functional foods and dietary supplements highlights the importance of systematic safety evaluation of these bioactive ingredients under high-dose exposure conditions. This study comprehensively evaluated the toxicological responses associated with total polyphenols from Cydonia oblonga Mill. (TPCOM) and explored their potential biological mechanisms. Ultra-high-performance liquid chromatography coupled with quadrupole-Orbitrap mass spectrometry identified 89 selected phenolic and related constituents. Acute and 28-day repeated-dose oral toxicity studies were conducted with reference to OECD Guideline 423 and in accordance with OECD Guideline 407, respectively. High-dose TPCOM exposure resulted in dose-associated biochemical and histopathological alterations, with the liver and kidneys identified as major target organs. Integrated systems toxicology approaches, including network toxicology, molecular docking, molecular dynamics simulations, and untargeted plasma metabolomics, revealed potential molecular targets, metabolic disturbances, and candidate biomarkers associated with TPCOM exposure. These findings suggest that excessive intake of TPCOM may be associated with metabolic imbalance, stress-related signaling alterations, and organ injury responses. Further experimental validation is required to confirm the specific molecular pathways involved. This study provides a systematic framework for evaluating the safety of polyphenol-rich functional food ingredients under high-dose exposure conditions.