Introduction:Hepatocellular carcinoma (HCC) is a highly malignant tumor characterized by considerable heterogeneity, aggressive invasiveness, and a high recurrence rate. Monotherapy often yields limited clinical efficacy, and evodiamine (EVO), a natural alkaloid with promising antitumor activity, is hindered by low bioavailability and potential systemic toxicity. Methods:A mesoporous polydopamine (MPDA)-based theranostic nanosystem was constructed for the co-delivery of EVO and the photothermal agent IR820. To enhance tumor specificity and minimize off-target toxicity, the platform was functionalized with cyclic RGD (cRGD) peptides for active tumor homing and triphenylphosphonium (TPP) for mitochondrial localization. The resulting IR820/EVO@MPDA-TPP/cRGD nanoparticles were characterized for drug loading, photothermal conversion stability, and fluorescence properties, and evaluated for antitumor efficacy and mechanistic actions in vivo. Results:The nanosystem demonstrated high drug loading efficiencies, excellent photothermal conversion stability, and robust near-infrared fluorescence emission suitable for real-time diagnostic tracing. Upon NIR laser irradiation, IR820/EVO@MPDA-TPP/cRGD exhibited potent synergistic anticancer activity and significantly inhibited tumor growth in vivo. Mechanistically, the combined photothermal and chemotherapeutic effects triggered severe mitochondrial dysfunction, leading to the collapse of mitochondrial membrane potential and subsequent release of pro-apoptotic factors. Discussion:The dual-targeting strategy effectively shifted cellular homeostasis toward programmed cell death while simultaneously engaging quality control pathways, underscoring a mitochondria-centered mechanism linking photothermal effect and chemotherapy. Conclusion:IR820/EVO@MPDA-TPP/cRGD represents a dual-targeting theranostic nanoplatform that integrates imaging and chemo-photothermal combination therapy. This strategy offers a promising and clinically relevant approach for advanced HCC.

Skin aging is a multifactorial biological process driven by oxidative stress (OS), chronic inflammation, cellular senescence, mitochondrial dysfunction, and non-enzymatic glycation (NEG), and is markedly accelerated by environmental stressors such as ultraviolet radiation (UVR) and air pollution. Natural bioactive compounds, including flavonoids, polyphenols, terpenoids, alkaloids, vitamins, polysaccharides, peptides, and indole derivatives, have demonstrated considerable potential in mitigating these processes through multi-target antioxidant, anti-inflammatory, anti-photoaging, and extracellular matrix (ECM)-protective mechanisms. However, their clinical and cosmetic translation is often limited by poor solubility, chemical instability, and insufficient skin penetration. Rather than providing a simple compilation of existing studies, this review offers a mechanism-oriented and delivery-driven synthesis of recent advances in natural anti-skin-aging research. We systematically integrate current knowledge on the molecular drivers of skin aging with a critical comparison of emerging transdermal and nanotechnology-based delivery systems, including lipid-based, polymer-based, inorganic/hybrid, and nucleic acid-assembled nanocarriers. Particular attention is given to how rational carrier design modulates stability, permeability, skin-layer targeting, and controlled release behavior. Furthermore, this review critically discusses current limitations, contradictory findings across studies, and key translational challenges, and identifies promising future research directions, such as stimuli-responsive systems, skin-layer-specific targeting, and mechanism-guided material selection. By bridging biological mechanisms with delivery material innovation, this work provides a forward-looking framework for the development of safer, more effective, and scientifically grounded anti-skin-aging therapeutics and cosmeceuticals. (c) 2026 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Osteoarthritis (OA) is a debilitating joint disorder that causes chronic pain, inflammation, and detrimental bone alterations. Despite significant advances in understanding OA pathogenesis, current therapeutic strategies remain inadequate in halting disease progression or providing effective pain relief, highlighting unmet clinical needs. Recent insights into OA nociceptive pathways, inflammatory mediators, and organelle dysfunction have revealed promising therapeutic targets. Specifically, OA progression is driven by mitochondrial dysfunction (marked by accumulated damaged mitochondria with excessive ROS production and impaired ATP synthesis), lysosomal destabilization (due to persistent hydroxyapatite digestion causing acidification loss, membrane permeabilization, and chondrocyte apoptosis), and unresolved ER stress (resulting from compensatory protein overproduction that exacerbates cartilage degradation). In this review, we aim to provide a comprehensive exploration of the nociceptive pathways linking the knee joint to the central nervous system, shedding light on the mechanisms underlying OA-associated pain. We further analyzed pathological changes in bone architecture and chondrocytes, emphasizing the synergistic roles of inflammatory cytokines and organelle-specific dysfunctions. Building on these mechanistic insights, we delineate emerging pharmacological strategies designed to concurrently address inflammatory cascades, restore organelle homeostasis (via mitophagy potentiation, lysosomal integrity preservation, and ER stress alleviation), and attenuate nociceptive signaling—thereby establishing a multimodal therapeutic paradigm to ameliorate both structural degeneration and clinical manifestations of OA. We also highlight advanced organelle-targeted drug delivery systems designed to increase the therapeutic efficacy and stability of these treatments. Collectively, these advancements provide a framework for novel OA interventions.

Diabetic colitis is a severe gastrointestinal complication of type 2 diabetes, which presents the key pathophysiological hallmarks of hyperglycemia, intestinal barrier disruption, immune dysregulation, and microbial metabolic imbalance, posing significant therapeutic challenges in clinical practice. Here, we leveraged artificial intelligence to identify the therapeutic potential of 1-deoxynojirimycin (DNJ) for addressing diabetic colitis. To improve its bioavailability and efficacy, we developed a mulberry-derived nanotherapeutic with surface functionalization of zwitterionic polymer (PpC) for DNJ encapsulation. Following oral administration, the resultant nanotherapeutics, PpC@DNJ-LNPs, efficiently traversed the gastrointestinal tract, enabling controlled DNJ release while inhibiting the α-glucosidase activity to regulate glucose homeostasis. Concurrently, they orchestrated colonic mucosa-microbiome interaction, promoting intestinal immune balance and microbiota remodeling. These synergistic effects collectively confer hypoglycemic, anti-inflammatory, antioxidant, and epithelial barrier-restoring effects, ultimately reshaping the glucose level and intestinal microecology. Our study demonstrates the translational potential of PpC@DNJ-LNPs as a safe and effective oral therapeutic platform for diabetic colitis.

Plant-derived extracellular vesicles (PDEVs) have attracted considerable attention as natural drug delivery vehicles owing to their low immunogenicity, excellent biocompatibility, cross-kingdom delivery capability and intrinsic targeting properties. They naturally encapsulate a variety of bioactive components that can synergize with loaded drugs, while the vesicles exhibit good stability under simulated gastrointestinal conditions. This review focuses on the structure-property-function relationships of PDEVs in drug delivery. It systematically compares current drug loading strategies and evaluation approaches, particularly engineered loading technologies and composite delivery systems. Furthermore, it summarizes the applications of PDEV-based delivery systems in disease therapy, vaccine development, cosmetics and nutraceuticals. Finally, we propose an evaluation framework to facilitate clinical translation, providing theoretical support for advancing these systems toward practical use.

Pediatric constipation, attributed to the functional immaturity of the gastrointestinal tract in children, is a common clinical disorder characterized by impaired gastrointestinal motility and infrequent bowel movements. Existing therapeutic strategies are frequently constrained by suboptimal efficacy owing to their single-target mechanisms and systemic toxicity. In contrast, Chinese medicinal formulas, with their multicomponent and multitarget intervention strategies, offer a highly suitable alternative for managing constipation. The traditional Chinese medicine formula "YiNianJin" (YNJ) is composed of cinnabar, rhubarb, stir-fried morning glory seeds, areca nut, and ginseng. It has demonstrated significant therapeutic efficacy in accelerating intestinal peristalsis through the synergistic regulation of aquaporin expression and the release of endocrine homeostatic transmitters. However, the clinical application of YNJ is significantly limited by conventional oral administration, which leads to Hg2+ accumulation and the low bioavailability of the active components. To address these challenges, we developed a sustained-release transdermal patch named YNJ patch (YNJP), which encapsulates cinnabar-loaded nanovesicles along with other active constituents in carboxymethyl cellulose sodium matrix. YNJP was shown to significantly enhance intestinal motility (as evidenced by a 24.02% increase in propulsion rate) by regulating the expression of mucin 2, aquaporin 3, and tight junction protein 1, while simultaneously promoting the release of endocrine homeostatic transmitters and Lactobacilli-mediated short-chain fatty acids. Therefore, YNJP is shown as a novel transdermal platform that alleviates pediatric constipation by modulating intestinal endocrine and metabolic homeostasis, enabling safe delivery of complex formulas with strong clinical potential for complex disorders.

BACKGROUND:Hepatocellular carcinoma (HCC) remains a global health challenge with limited treatment options and frequent development of drug resistance. Sophora flavescens, a traditional Chinese medicine, contains prenylated flavonoids with documented antitumor potential, though their in vivo efficacy and precise molecular mechanisms against HCC remain largely unexplored. PURPOSE:This study aimed to systematically evaluate the anti-HCC activity of prenylated flavonoids in S. flavescens (PFS), identify the key bioactive constituents, and elucidate the underlying molecular mechanisms. METHODS:The chemical profile of PFS extract was characterized using UHPLC-QE-Orbitrap MS. Anti-HCC effects were assessed in vitro through cell viability, proliferation, migration, cell cycle, apoptosis, and mitochondrial function assays. An in vivo HepG2 cell-derived xenograft model was employed to evaluate tumor growth inhibition and safety. Mechanistic insights were gained via proteomics, western blotting, and in silico analysis. RESULTS:Forty-one prenylated flavonoids were identified in the extract. PFS significantly inhibited HCC cell proliferation and migration, induced cell cycle arrest, apoptosis, and mitochondrial dysfunction in vitro, and suppressed tumor growth in vivo with a favorable safety profile. Proteomic and Western blot analyses revealed that PFS mediates mitochondrial apoptosis by downregulating p-Akt and p-MDM2, upregulating p53 and NOXA, disrupting the Bax/Bcl-2 balance, and activating the cytochrome c/Caspase-3/PARP1 cascade. In silico analysis further suggested C8-prenylated flavonoids, notably (2R,3R)-5-Methoxy-7,4'-dihydroxy-8-[3,3-dimethylallyl]-flavanonol (17), Kushenol M (33), and 2'‑methoxy kushenol I (34), might be the key active components targeting the Akt/MDM2/p53 pathway. CONCLUSION:This study demonstrates that PFS inhibit HCC growth by inducing mitochondrial apoptosis via suppression of the Akt/MDM2/p53 signaling pathway. PFS represents a promising candidate for further development as a complementary therapy for HCC.

Compared to synthetic chemical compounds, plant extracts derived from natural sources have emerged as the "new favorites" in the treatment and care of skin diseases due to their distinct advantages, including being environmentally friendly, sustainable, and safe. However, challenges such as poor solubility, limited permeability, and the barrier function of the stratum corneum significantly restrict the application of natural products in dermal drug delivery. Fortunately, advancements in nanotechnology offer promising solutions to overcome these challenges. Different skin diseases and treatments require the precise delivery of natural active ingredients to specific skin layers, and the unique structure of nanocarriers enables targeted delivery to achieve desired therapeutic outcomes. This paper begins by exploring the pathogenesis and therapeutic targets of common skin conditions, including atopic dermatitis (AD), psoriasis, decubitus ulcers, diabetic foot ulcers (DFUs), as well as applications in antioxidant therapies and anti-aging strategies. Furthermore, it provides a detailed overview of the depths and locations within the skin where active compounds must be delivered to exert their effects effectively. Subsequently, this review categorizes and examines natural products based on their therapeutic effects on various skin diseases. It then highlights the skin depths and specific sites that can be targeted by different delivery systems designed to enhance skin permeability, tailored to meet the needs of skin disease treatment or care. By addressing these aspects, this review aims to provide a valuable reference for advancing research on nano-delivery systems in the field of topical skin drug delivery for the treatment and management of skin diseases.

Background:Hepatocellular carcinoma (HCC) is notorious for its dismal prognosis and resistance to conventional therapies. The integration of multiple cell death mechanisms emerges as a promising strategy to combat the heterogeneity of this malignancy. Purpose:Herein, we engineered a multifunctional nanoplatform, TPMIL101-TCPP@Lip-HA, by encapsulating the photosensitizer TCPP and chemotherapeutic agent triptolide (TP) within a metal-organic framework (MIL101), followed by surface modification with liposomes and hyaluronic acid. This sophisticated drug delivery system capitalizes on the enhanced permeability and retention effect to achieve tumor-specific accumulation. Methods:Upon reaching the tumor site, TPMIL101-TCPP@Lip-HA undergoes gradual disintegration, releasing its therapeutic payload. The tumor microenvironment facilitates the reduction of Fe³⁺ to Fe²⁺, triggering ferroptosis through the Fenton reaction. Simultaneously, laser irradiation activates TCPP to generate cytotoxic reactive oxygen species, initiating photodynamic therapy-induced apoptosis. The concomitant accumulation of lipid peroxides synergistically amplifies the ferroptotic cascade. Results:In vitro/in vivo studies confirm potent anti-HCC efficacy with reduced TP toxicity. Mechanistic studies elucidate that TPMIL101-TCPP@Lip-HA orchestrates ferroptosis through modulation of iron storage and lipid oxidation proteins, while concurrently inducing apoptosis via the cytochrome c/Apaf-1/caspase signaling axis. Conclusion:These findings collectively underscore TPMIL101-TCPP@Lip-HA as a potent therapeutic nanoplatform capable of arresting HCC progression.

BACKGROUND:Polycystic ovary syndrome (PCOS) is a neuroendocrine-metabolic disorder with no approved drugs. Hypothalamic-pituitary-ovarian (HPO) axis dysfunction is core pathogenesis, and metabolic heterogeneity complicates treatment. Existing medications rarely ameliorate PCOS comprehensively. Sangzhi alkaloids (SZ-A), an extract from Morus alba L. twigs approved for type 2 diabetes in China, have not been systematically explored for PCOS. PURPOSE:To clarify the therapeutic effect and the mechanisms of SZ-A in PCOS. STUDY DESIGN:Animal studies, in vitro experiments and a placebo-controlled clinical trial. MATERIALS AND METHODS:In vivo: Obese/non-obese PCOS rats received oral SZ-A 67, 100, 150 mg/(kg·d) for 21 days (positive controls: Diane-35, metformin). In vitro: Granulosa cell apoptosis induced by dihydrotestosterone was treated with SZ-A 25, 50, 100, 200 μg/ml. CLINICAL:6-month placebo-controlled trial (128 PCOS patients; oral SZ-A 300 mg/d, n = 88; placebo, n = 40). Multi-omics/Western blotting explored HPO pathways. RESULTS AND DISCUSSION:In rats, SZ-A (67 to 150 mg/(kg·d), 21 days) dose-dependently reduced androgens, regularized estrous cycles, and improved ovarian morphology. In vitro, SZ-A (25 to 200 μg/ml) protected granulosa cells from apoptosis. In patients, 6-month SZ-A (300 mg/d) lowered free androgen index and improved menstrual regularity versus placebo. Mechanistically, SZ-A inhibited hyperandrogenism-induced granulosa cell apoptosis and regulated GnRH secretion and downstream signaling pathways. CONCLUSION:SZ-A exerts therapeutic effects on PCOS by modulating HPO axis function through multiple pathways. TRIAL REGISTRATION:ChiCTR2200065097.

Triple-negative breast cancer (TNBC) is recognized as the notoriously difficult molecular subtype of breast cancer to manage therapeutically, creating a pressing need for more effective treatment approaches. Immunochemotherapy is an emerging strategy with great clinical potential, but most focus on the tumor microenvironment itself and ignore the immune regulation of lymph nodes. Herewith, we report a dual-pronged approach of tumor-targeted paclitaxel-encapsulated nanoemulsion (PTX Emul, Phase II clinical trial) and lymph node-targeted chlorogenic acid-encapsulated self-emulsifying nanocarriers (CHA-SME) to elicit strong and selective immunogenic cell death (ICD) in the tumor and to activate immune cells in the lymph nodes, respectively, to achieve highly effective cancer immunotherapy. PTX Emul exhibited evident tumor targetability and superior tumor accumulation, induced potent ICD, and then efficiently stimulated the maturation of dendritic cells (DCs). CHA-SME demonstrates a substantial capacity to enhance drug accumulation within the mesenteric lymph nodes through the lymphatic transport pathway. Of note, PTX Emul combined with CHA-SME augmented the immunotherapeutic effects through highly efficient ICD induction within the tumor microenvironment of 4T1 orthotopic tumor, the potent DC maturation, and the effective activation of T cell-based antitumor immunity, resulting in a substantial enhancement in the inhibition of 4T1 orthotopic tumors and, notably, a reduction in lung metastasis. The dual-pronged approach of TNBC-targeted PTX Emul and lymph node-targeted CHA-SME by inducing ICD and activating lymphoid immune cells, which amplifies the systemic antitumor immune response, provides an interesting platform for potent immunochemotherapy of TNBC.

Chronic wounds are often difficult to heal because of multiple pathological barriers, including infection, vascular insufficiency, and immune imbalance, and therefore require highly effective dressings to promote repair. Chitosan (CS), a cationic polysaccharide derived from the deacetylation of chitin, has attracted broad attention in wound management because of its favorable biocompatibility, biodegradability, chemical modifiability, and intrinsic hemostatic and antibacterial activities. The therapeutic value of CS-based dressings does not depend solely on CS itself, but rather on their ability to target the dominant pathological barriers of different wound types through structural modification and formulation design. This review links the key pathological features of various chronic wounds with the functional requirements of CS-based dressings, and systematically summarizes how modification strategies such as catechol grafting, quaternization, carboxymethylation, and dynamic covalent crosslinking regulate the properties of CS, as well as the major fabrication platforms and formulation types, including crosslinked hydrogels, freeze-dried sponges, electrospun nanofibers, phase-inversion membranes, and solvent-cast films. Their effects on porosity, mechanical strength, moisture retention, and permeability are also analyzed. Finally, the review discusses the challenges facing CS-based dressings in standardization, scalable manufacturing, clinical translation, and regulatory evaluation, and highlights the need for greater emphasis on multifunctional smart design and the improvement of evidence quality in future research.

Diabetic wounds, characterized by a complex pathological microenvironment of persistent inflammation, impaired angiogenesis, and dysfunctional extracellular matrix (ECM) remodeling, pose a significant clinical challenge due to the lack of highly effective treatments. Given that simultaneous modulation of these interconnected pathological processes is crucial for effective healing, a multifunctional hydrogel dressing (SQS-GEL) with self-healing and pH-responsive properties was engineered for the targeted delivery of exosome-like nanovesicles derived from Ramulus Mori (SZENs). This dual-network hydrogel was constructed through dynamic Schiff base bonds between oxidized mulberry branch polysaccharides and quaternized chitosan, further reinforced by hydrogen bonding interactions with silk fibroin. The resulting SQS-GEL exhibited excellent mechanical strength, injectability, and autonomous self-healing capability. Crucially, it demonstrated intelligent pH-dependent degradation property, enabling controlled release of SZENs specifically in the acidic wound microenvironment. In vitro studies revealed that the SZENs@SQS-GEL system synergistically enhanced antioxidant and anti-inflammatory activities, while potently promoting cell proliferation, migration, and angiogenesis. In a streptozotocin-induced diabetic mouse model, the hydrogel significantly prolonged SZENs retention at the wound site. This led to multifaceted therapeutic outcomes: effective bacterial inhibition, alleviation of excessive inflammation, stimulation of granulation tissue formation, enhanced angiogenesis, and facilitated orderly ECM deposition. Consequently, SZENs@SQS-GEL dramatically accelerated wound closure and promoted scarless healing. This study presents a novel and integrated therapeutic strategy, highlighting the great translational potential of the SZENs@SQS-GEL system for managing refractory diabetic wounds and other inflammatory tissue disorders.

Cutaneous injuries, a prevalent clinical challenge, often face delayed healing due to suboptimal wound management strategies. Conventional hydrogel dressings are limited by inadequate mechanical properties, poor bioactivity, and insufficient therapeutic efficacy. Here, we developed an innovative in situ forming hydrogel dressing by integrating silk fibroin (SF)-a natural biopolymer with tunable structural and bioactive properties-with polyvinyl butyral (PVB), which provides an ideal system for the delivery of active substances for wound healing and has broad application prospects in skin wound management. Upon ethanol evaporation, the SF/PVB composite rapidly formed a hydrogel film with enhanced mechanical strength, optimal breathability, and waterproofness. The SF-based dressing (LD-SF) demonstrated multifunctional wound-healing capabilities, including rapid hemostasis, antioxidative activity, and anti-inflammatory modulation. Notably, molecular-weight (MW)-dependent bioactivity was observed: low-MW SF (45 kDa) significantly promoted fibroblast proliferation and migration, while high-MW SF (72 kDa) exhibited superior immunomodulatory effects by polarizing macrophages toward pro-resolving phenotypes. In a murine full-thickness wound model, LD-SF accelerated re-epithelialization, enhanced angiogenesis, and stimulated collagen remodeling. Mechanistically, LD-SF facilitated extracellular matrix regeneration via β-sheet-driven structural stability and amino acid-mediated metabolic support. This dual-action system synergistically orchestrates immunomodulation-through macrophage phenotype regulation and cytokine balance-and robust extracellular matrix regeneration, offering a transformative approach to acute wound repair with minimized scarring and accelerated functional recovery. The study provides a clinically translatable solution for acute wound care by integrating rapid in situ film formation, molecular-weight-tunable bioactivity, and scar-minimizing outcomes, thereby addressing critical gaps in current wound management technologies.

Cancer immunotherapy has emerged as a promising strategy. However, low response rates and immune-related side effects have plagued immunotherapy. Metallic nanoparticles, utilizing metals as their framework, are gaining prominence in cancer immunotherapy. Metal ions have shown the ability to modulate immune status by activating the cGAS-STING pathway and inducing immunogenic cell death (ICD), thereby enabling multidimensional activation of immunotherapy. Metallic nanoparticles offer significant advantages in cancer immunotherapy, leading to their increasing use in enhancing therapeutic outcomes. In view of the ever-increasing research on metallic nanoparticles, this review presents the construction, characterization, and enhanced cancer immunotherapeutic effects of different types of metal nanosystems from the perspective of the immunoregulatory mechanisms of metal ions. We delve into the current limitations and future directions of metallic nanoparticles in this rapidly evolving field. To the best of our knowledge, this review offers the most up-to-date and systematic analysis of metallic nanoparticles in immunotherapeutic applications. It is anticipated that this review of metallic nanoparticles will inspire a more refined and intelligent design of metallic nanoparticles for future research, paving the way for advancing their clinical applications.

Prenylated flavonoids in Sophora flavescens (PFS) are unique chemical constituents that possess significant antiinflammatory activity despite their low content, which has great potential to be transformed into lead compounds. In recent years, there has been an increasing focus on its extraction. Ultrasound-assisted extraction (UAE) has been widely used in the extraction of natural products due to its high efficiency, economy, and green chemical concept. The objective of this study was to extract PFS by ultrasonic-assisted extraction. The extraction process was optimized by a single-factor test and response surface design, resulting in a total yield of PFS at 5.97 mg/g under the following conditions: a liquid-to-material ratio of 26 mL/g, ethanol concentration of 90 %, extraction time of 28 min, and ultrasonic power of 640 W. The PFS extract, when extracted under optimal conditions, displayed strong 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and 2, 2 '-azino-bis (3-ethylbenzothiazoline6-sulfonate) radical cation (ABTS) free radical scavenging and iron ion reduction abilities. Subsequent in vitro experiments demonstrated that PFS ameliorated lipopolysaccharide-induced inflammation and oxidative stress in RAW264.7 cells in a dose-dependent manner. Furthermore, the mechanism of UAE was characterized using scanning electron microscopy and Fourier transform infrared spectroscopy. It was determined that ethanol and ultrasonic treatment damaged plant cell walls, improved mass transfer and diffusion, and promoted the dissolution of PFS. In conclusion, this investigation highlights the application of UAE in optimizing the yield of PFS and confirms the strong anti-inflammatory and antioxidant activities of PFS. Additionally, the mechanism of UAE was elucidated. It establishes the scientific theoretical foundation for PFS in industrial production and application.

This study presents the first development and validation of a static multiple light scattering (SMLS)-based method for real-time, non-invasive assessment of nanoparticle colloidal stability. Nanoparticles, leveraging their nanoscale advantages (e.g., targeted delivery, enhanced drug solubility, and controlled release), hold transformative potential in treating diseases. However, their clinical success hinges on colloidal stability, which dictates in vivo behavior, safety, and regulatory compliance. While dynamic light scattering (DLS) remains widely used, its inability to monitor dynamic transformations and reliance on sample dilution limit its accuracy. Here, we pioneer the application of SMLS to systematically evaluate colloidal stability across standardized particles and commercial nanoparticle formulations (liposomes, nanoparticles, micelles, and nanoemulsions). Results demonstrate that SMLS captures destabilization kinetics (aggregation, sedimentation, and creaming) in real-time without dilution, even at high concentrations, while DLS fails to distinguish polydisperse systems due to time-point sampling. The Turbiscan stability index (TSI) quantifies instability mechanisms, correlating with particle size distribution broadening. This first comprehensive validation of SMLS for nanoparticles reveals its superiority in reflecting native-state behavior, exemplified by minimal or the variations in the average transmission (ΔT) or backscattering intensity (ΔBS) fluctuations and low TSI values in four commercial formulations. By addressing a critical technological gap, this study establishes SMLS as an indispensable tool for optimizing nanoparticle design, ensuring compliance with U.S. Food and Drug Administration (FDA) in-use stability guidelines, and accelerating clinical translation.

Insomnia is a prevalent sleep disorder and it affects brain development, with pediatric populations being particularly vulnerable. Cinnabar, a mineral drug composed of HgS, has demonstrated efficacy in alleviating insomnia through suppressing the overactivity of glutamate receptors (NMDA/AMPA), etc. However, oral administration of cinnabar poses risks, including binding with hemoglobin and accumulation in tissues and organs, resulting in neurotoxicity. To overcome these limitations, we developed a novel transdermal and intestinal targeting programmed nanoplatform for cinnabar delivery (TAT/CSK-cinnabar vesicle, TCCV), of which, cinnabar was encapsulated within a lipid vesicle, which was then co-engineered with cell-penetrating peptide TAT and the intestinal-targeting CSK ligand. Accordingly, TCCV showed exceptional sequential penetration through the stratum corneum (SC) and intestinal barriers, and also actively targeted intestinal goblet cells with a 15-fold increase in efficiency compared to non-engineered vesicles. Furthermore, TCCV forms a reservoir releasing cinnabar at the intestinal site with controlled manner, significantly reducing fluctuations in cinnabar concentration in blood and organs, thereby reducing toxicity. In current anti-insomnia studies, TCCV exhibited predominantly enhanced therapeutic efficiency compared to the oral control group, with drug efficiency increased by 1.5 to 2.5-fold. With the analysis of RNA sequencing and 16S rRNA, the regulation of the serotonin (5-HT) production in gut microbes and activating the Htr1d-cAMP pathway of cerebral cortex through the ''brain-gut axis'' by TCCV is identified as the novel mechanism for the insomnia mitigation effect of cinnabar. This study offers a novel non-invasive transdermal and targeted nanoplatform that significantly improves the efficacy and biosafety of cinnabar delivery and highlights a new gut-brain axis-mediated mechanism in insomnia mitigation.