A Self-Amplifying ROS-Responsive Nanoplatform for Simultaneous Cuproptosis and Cancer Immunotherapy.

Cuproptosis is an emerging cell death pathway that depends on the intracellular Cu ions. Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and trigger cuproptosis. However, ES can be rapidly removed and metabolized during intravenous administration, leading to a short half-life and limited tumor accumulation, which hampers its clinical application. Here, the study develops a reactive oxygen species (ROS)-responsive polymer (PCP) based on cinnamaldehyde (CA) and polyethylene glycol (PEG) to encapsulate ES-Cu compound (EC), forming ECPCP. ECPCP significantly prolongs the systemic circulation of EC and enhances its tumor accumulation. After cellular internalization, the PCP coating stimulatingly dissociates exposing to the high-level ROS, and releases ES and Cu, thereby triggering cell death via cuproptosis. Meanwhile, Cu2+-stimulated Fenton-like reaction together with CA-stimulated ROS production simultaneously breaks the redox homeostasis, which compensates for the insufficient oxidative stress treated with ES alone, in turn inducing immunogenic cell death of tumor cells, achieving simultaneous cuproptosis and immunotherapy. Furthermore, the excessive ROS accelerates the stimuli-dissociation of ECPCP, forming a positive feedback therapy loop against tumor self-alleviation. Therefore, ECPCP as a nanoplatform for cuproptosis and immunotherapy improves the dual antitumor mechanism of ES and provides a potential optimization for ES clinical application.

Glutamate affects self-assembly, protein corona, and anti-4 T1 tumor effects of melittin/vitamin E-succinic acid-(glutamate)n nanoparticles.

Melittin (M) has attracted increasing attention for its significant antitumor effects and various immunomodulatory effects. However, various obstacles such as the short plasma half-life and adverse reactions restrict its application. This study aimed to systematically investigate the self-assembly mechanism, components of the protein corona, targeting behavior, and anti-4 T1 tumor effect of vitamin E-succinic acid-(glutamate)n /melittin nanoparticles with varying amounts of glutamic acid. Here, we present a new vitamin E-succinic acid-(glutamate)5 (E5), vitamin E-succinic acid-(glutamate)10 (E10) or vitamin E-succinic acid-(glutamate)15 (E15), and their co-assembly system with positively charged melittin in water. The molecular dynamics simulations demonstrated that the electrostatic energy and van der Waals force in the system decreased significantly with the increase in the amount of glutamic acid. The melittin and E15 system exhibited the optimal stability for nanoparticle self-assembly. When nanoparticles derived from different self-assembly systems were co-incubated with plasma from patients with breast cancer, the protein corona showed heterogeneity. In vivo imaging demonstrated that an increase in the number of glutamic acid residues enhanced circulation duration and tumor-targeting effects. Both in vitro and in vivo antitumor evaluation indicated a significant increase in the antitumor effect with the addition of glutamic acid. According to our research findings, the number of glutamic acid residues plays a crucial role in the targeted delivery of melittin for immunomodulation and inhibition of 4 T1 breast cancer. Due to the self-assembly capabilities of vitamin E-succinic acid-(glutamate)n in water, these nanoparticles carry significant potential for delivering cationic peptides such as melittin.

Sulfated hyaluronic acid gel for the treatment of rheumatoid arthritis in rats.

Rheumatoid arthritis (RA) is a chronic autoimmune disease. NSAIDS, cyclophosphamide and glucocorticoid were commonly used to treat RA in clinical application, which long-term administration of these drugs caused serious adverse reactions. Therefore, sulfated hyaluronic acid (sHA) gel (SG) was prepared to firstly treat the RA and avoid the problem of toxic side effect caused by long-term application. In vitro evaluation showed that sHA inhibited the level of reactive oxygen species and TNF-α, IL-1ß, and IL-6, and decreased the ratio of macrophage M1/M2 type, which exerted better anti-inflammatory capacity. In vivo studies showed that the injection of SG into the joint cavity of collagen-induced rheumatoid arthritis (CIA) rats could effectively treat joint swelling and reduce the level of inflammatory factors in the serum. Immunofluorescence showed that SG exerted its anti-inflammatory activity by decreasing the ratio of M1/M2 type macrophages in synovial tissue. Cartilage tissue sections showed that SG reduced bone erosion and elevated chondrocyte expression. These results confirmed that sHA is expected to be developed as a drug to treat or relieve RA, which could effectively regulate the level of macrophages in rat RA, alleviate the physiological state of inflammatory over-excitation, and improve its anti-inflammatory and antioxidant capacity.

Potential effects of sodium hyaluronate on constipation-predominant irritable bowel syndrome.

Treatment strategies for constipation-predominant irritable bowel syndrome (IBS-C) continue to improve. However, effective drugs are still lacking. Herein, we explored whether sodium hyaluronate (SH) could be used to treat IBS-C. The effects of SH with different molecular weights were compared in a rat model of IBS-C. Low-molecular-weight SH (LMW-SH, 5 âˆ¼ 10 kDa), medium-molecular-weight SH (MMW-SH, 200 âˆ¼ 400 kDa), and high-molecular-weight SH (HMW-SH, 1300 âˆ¼ 1500 kDa) were screened for efficacy in IBS-C using the following indicators: body weight, number of fecal pellets, fecal moisture, visceral hypersensitivity, and gastrointestinal transit rate. H-HMW-SH was the most effective in improving IBS-C symptoms. The ELISA kits indicated that H-HMW-SH reduced the levels of pro-inflammatory cytokines IL-1ß, IL-18, and TNF-α in IBS-C rats. In addition, both western blot and immunofluorescence analyses showed that H-HMW-SH increased the protein expressions of claudin-1, occludin and zonula occludens-1. Furthermore, H-HMW-SH restored the balance of intestinal flora in different intestinal contents (duodenum, jejunum, ileum, and colon) and feces of rats with IBS-C. Overall, our study illustrates the therapeutic potential of H-HMW-SH in the treatment of IBS-C.

Explore the underlying oral efficacy of α-, ß-, γ-Cyclodextrin against the ulcerative colitis using in vitro and in vivo studies assisted by network pharmacology.

The incidence of ulcerative colitis (UC) is rising worldwide. As a refractory and recurrent disease, UC could seriously affect the patients' quality of life. However, current clinical medical treatments for UC are accompanied by various side effects, especially for long-term applications. Here, the underlying efficacy of cyclodextrins (CDs) was studied. As common excipients, CDs endow proven safety for long-term applications. Results of predictive methods derived from network pharmacology prompted the potential anti-inflammatory effects of CDs by oral administration. RAW264.7 cell experiments verified that CDs could inhibit the excessive secretion of TNF-α (ß-CD > α-CD ≈ γ-CD), IL-6, and NO (α-CD > ß-CD ≈ γ-CD) as predicted. In mice with DSS-induced acute UC, oral administration of CDs could effectively mitigate the pathological damage of colon tissue and reduce the level of inflammatory mediators. Moreover, 16S rRNA sequencing displayed that gut microbes disturbed by DSS were significantly regulated by CDs. Conclusively, the study showed the therapeutic application prospects of CDs in UC treatment and indicated the feasibility and advantages of developing 'new' therapeutic activities of 'old' ingredients.Communicated by Ramaswamy H. Sarma.

Influence of cryopreservation methods of ex vivo rat and pig skin on the results of in vitro permeation test.

In vitro permeation test (IVPT) is a frequently used method for in vitro assessment of topical preparations and transdermal drug delivery systems. However, the storage of ex vivo skin for IVPT remains a challenge. Here, two cryopreservation media were chosen to preserve rat and pig skin at -20 °C and -80 °C for further IVPT, namely, 10 % DMSO and 10 % GLY. The skin viability test confirmed that the skin protective capacity of 10 % DMSO and 10 % GLY was almost equal. The results of skin viability and IVPT showed that the skin viability and permeability of rat skin in 10 %DMSO or 10 % GLY were maintained for at least 7 and 30 days at -20 °C and -80 °C compared to fresh skin, respectively; in contrast, those of porcine skin were just maintained for <7 days at -20 °C and -80 °C. These results indicated that ex vivo skin for IVPT preserved at -80 °C in 10 % DMSO or 10 % GLY was optimal. Furthermore, skin permeability was independent of skin barrier integrity. Our study provides reference conditions for preserving IVPT skin, and skin viability can be a potential indicator of IVPT skin.

Hyaluronic acid and HA-modified cationic liposomes for promoting skin penetration and retention.

Hyaluronic acid (HA) has been widely used in cosmetics and topical preparations owing to its favorable moisturizing property and potential in enhancing drugs' skin permeability. Here, the influencing factors and underlying mechanism of HA on skin penetration were carefully investigated, and HA-modified Undecylenoyl-Phenylalanine (UP) liposomes (HA-UP-LPs) were designed as a proof of principle for efficacious transdermal drug delivery strategy to enhance the skin penetration and retention. An in vitro penetration test (IVPT) of HA with different molecular weights showed that low molecular weight HA (LMW-HA, 5 kDa and 8 kDa) could pass through the stratum corneum (SC) barrier and enter into the epidermis and dermis layers, whereas its high molecular counterparts (HMW-HA) were trapped on the SC surface. Mechanistic studies revealed that LMW-HA could interact with keratin and lipid in the SC meanwhile exerted a substantial skin hydration effect, which may partially contribute to the SC penetration benefit. In addition, the surface decoration of HA drove an energy-dependent caveolae/lipid raft-mediated endocytosis of the liposomes through direct binding to the CD44 receptors widely expressed on skin cell membranes. Notably, IVPT showed a 1.36-fold and 4.86-fold increase in skin retention of UP and a 1.62-fold and 5.41-fold increase in skin penetration of UP with HA-UP-LPs over UP-LPs and free UP at 24 h, respectively. As a result, the anionic HA-UP-LPs (-30.0 mV) showed enhanced drug skin penetration and retention compared with conventional cationic bared UP-LPs (+21.3 mV) on both in vitro mini-pig skin as well as in vivo mouse skin. Overall, the usage of LMW-HA might offer opportunities in developing novel topical preparations and skin care products with improved transdermal penetration and retention.

Supersaturation and Precipitation Applicated in Drug Delivery Systems: Development Strategies and Evaluation Approaches.

Supersaturation is a promising strategy to improve gastrointestinal absorption of poorly water-soluble drugs. Supersaturation is a metastable state and therefore dissolved drugs often quickly precipitate again. Precipitation inhibitors can prolong the metastable state. Supersaturating drug delivery systems (SDDS) are commonly formulated with precipitation inhibitors, hence the supersaturation is effectively prolonged for absorption, leading to improved bioavailability. This review summarizes the theory of and systemic insight into supersaturation, with the emphasis on biopharmaceutical aspects. Supersaturation research has developed from the generation of supersaturation (pH-shift, prodrug and SDDS) and the inhibition of precipitation (the mechanism of precipitation, the character of precipitation inhibitors and screening precipitation inhibitors). Then, the evaluation approaches to SDDS are discussed, including in vitro, in vivo and in silico studies and in vitro-in vivo correlations. In vitro aspects involve biorelevant medium, biomimetic apparatus and characterization instruments; in vivo aspects involve oral absorption, intestinal perfusion and intestinal content aspiration and in silico aspects involve molecular dynamics simulation and pharmacokinetic simulation. More physiological data of in vitro studies should be taken into account to simulate the in vivo environment. The supersaturation theory should be further completed, especially with regard to physiological conditions.

Chlorella sp.-ameliorated undesirable microenvironment promotes diabetic wound healing.

Chronic diabetic wound remains a critical challenge suffering from the complicated negative microenvironments, such as high-glucose, excessive reactive oxygen species (ROS), hypoxia and malnutrition. Unfortunately, few strategies have been developed to ameliorate the multiple microenvironments simultaneously. In this study, Chlorella sp. (Chlorella) hydrogels were prepared against diabetic wounds. In vitro experiments demonstrated that living Chlorella could produce dissolved oxygen by photosynthesis, actively consume glucose and deplete ROS with the inherent antioxidants, during the daytime. At night, Chlorella was inactivated in situ by chlorine dioxide with human-body harmless concentration to utilize its abundant contents. It was verified in vitro that the inactivated-Chlorella could supply nutrition, relieve inflammation and terminate the oxygen-consumption of Chlorella-respiration. The advantages of living Chlorella and its contents were integrated ingeniously. The abovementioned functions were proven to accelerate cell proliferation, migration and angiogenesis in vitro. Then, streptozotocin-induced diabetic mice were employed for further validation. The in vivo outcomes confirmed that Chlorella could ameliorate the undesirable microenvironments, including hypoxia, high-glucose, excessive-ROS and chronic inflammation, thereby synergistically promoting tissue regeneration. Given the results above, Chlorella is considered as a tailor-made therapeutic strategy for diabetic wound healing.

A Triptycene-Based 2D MOF with Vertically Extended Structure for Improving the Electrocatalytic Performance of CO2 to Methane.

Two-dimensional conductive metal-organic frameworks (2D-c-MOFs) have attracted extensive attention owing to their unique structures and physical-chemical properties. However, the planarly extended structure of 2D-c-MOFs usually limited the accessibility of the active sites. Herein, we designed a triptycene-based 2D vertically conductive MOF (2D-vc-MOF) by coordinating 2,3,6,7,14,15-hexahydroxyltriptycene (HHTC) with Cu2+ . The vertically extended 2D-vc-MOF(Cu) possesses a weak interlayer interaction, which leads to a facile exfoliation to the nanosheet. Compared with the classical 2D-c-MOFs with planarly extended 2D structures, 2D-vc-MOF(Cu) exhibits a 100 % increased catalytic activity in terms of turnover number and a two-fold increased selectivity. Density functional theory (DFT) calculations further revealed that higher activity originated from the lower energy barriers of the vertically extended 2D structures during the CO2 reduction reaction process.

Sodium hyaluronates applied in the face affects the diversity of skin microbiota in healthy people.

OBJECTIVE: A healthy and stable microbiome has many beneficial effects on the host, while an unbalanced or disordered microbiome can lead to various skin diseases. Hyaluronic acid is widely used in the cosmetics and pharmaceutical industries; however, specific reports on its effect on the skin microflora of healthy people have not been published. This study aimed to determine the effect of sodium hyaluronate on the facial microflora of healthy individuals. METHODS: Face of 20 healthy female volunteers between 18 and 24 years was smeared with sodium hyaluronate solution once per day. Cotton swabs were used to retrieve samples on days 0, 14, and 28, and high-throughput sequencing of 16 S rRNA was used to determine the changes in bacterial community composition. RESULTS: Facial application of HA can reduce the abundance of pathogenic bacteria, such as Cutibacterium and S. aureus, and increase the colonization of beneficial bacteria. CONCLUSION: This is the first intuitive report to demonstrate the effect of hyaluronic acid on facial microflora in healthy people. Accordingly, sodium hyaluronate was found to have a positive effect on facial skin health.

Study on the preparation of EGCG-γ-Cyclodextrin inclusion complex and its drug-excipient combined therapeutic effects on the treatment of DSS-induced acute ulcerative colitis in mice.

In this study, γ-cyclodextrins (γ-CD) and epigallocatechin-3-gallate (EGCG) were designed to form an inclusion complex (EGCG-γ-IC) for ulcerative colitis (UC) treatment. The drug-excipient combined therapeutic potential of γ-CD and EGCG was verified, when stability and compliance were also achieved. EGCG-γ-IC effectively inhibited the secretions of NO, TNF-α, and IL-6 and the intracellular ROS in RAW264.7 cells. The effectiveness of EGCG-γ-IC in treating DSS-induced acute UC in mice was observed including improving the histological conditions of the colon, reducing the levels of IL-1ß, IL-6, and TNF-α in serum, and restoring MPO, GSH, and sIgA levels in intestinal tissues. Moreover, EGCG-γ-IC had a more prominent effect on regulating bacterial dysbiosis caused by DSS than EGCG and γ-CD alone. Therefore, EGCG-γ-IC designed here displayed UC treating capacity with safety in the long-term application and promised an industrial production potential due to its excellent storage stability.

Hyaluronic acid-cyclodextrin encapsulating paeonol for treatment of atopic dermatitis.

The cyclodextrin (CD) was grafted onto hyaluronic acid (HA) to form a topical delivery carrier (HACD) in which Paeonol was loaded in its CD cavity and self-assemble into the polymeric micelles (HACD-PAE) for the treatment of atopic dermatitis. Fluorescence microscope observed that HACD could fast penetrate into the skin and remain stable within 12 h. In vitro penetration test (IVPT) results showed the PAE retentions of HACD-PAE group in the stratum corneum and dermis were 3.35 and 1.78 times improvement than that of PAE group. ATR-FTIR and H&E staining assays indicated HACD could increase the gap of keratinocytes by interacting with corneum lipids and loosening the keratin. Furthermore, HACD-PAE showed the best therapeutic effect on atopic dermatitis mice. Thus HACD could be a promising skin-specific delivery carrier, not only promoting the drug penetrating but increasing its remaining in the skin and play the skin disease therapy and skin-care role.

Oxybutynin nanosuspension gel for enhanced transdermal treatment for overactive bladder syndrome.

Oxybutynin (OXY) is the most common drug to treat overactive bladder (OAB) syndrome. Transdermal administration is a more ideal route replacing oral administration to resolve problems of low bioavailability and severe side effects. However, commercial transdermal products of OXY frequently cause skin irritation and low permeation efficiency arising discontinued medication. Here, oxybutynin nanosuspension (OXY-NS) and its gel preparation (OXY-NG) were constructed to resolve these issues. In vitro permeation test and in vivo pharmacokinetics study confirmed that OXY-NG significantly enhanced the transdermal permeation of OXY, about 4-fold and 3-fold higher than oxybutynin coarse suspension (OXY-CG), respectively, and in vitro retention test certified that OXY-NG increased OXY concentration especially in viable epidermis (VE) and Dermis (about 3 times that of OXY-CG), consequently improving the bioavailability. Skin irritation assay demonstrated that OXY-NG would not trigger skin adverse effects. In addition, selectively blocking hair follicles test evidenced that hair follicles pathway played an important role in OXY-NS transdermal delivery. In general, by virtue of excellent drug loading, low toxicity and ease of scale-up, OXY-NG is a promising strategy to ameliorate skin permeation of insoluble OXY for better transdermal treatment for OAB, hence increasing its bioavailability, reducing adverse effects, and achieving good patient compliance.

Honokiol nanosuspensions loaded thermosensitive hydrogels as the local delivery system in combination with systemic paclitaxel for synergistic therapy of breast cancer.

Local administration of therapeutic agents provides a favorable approach to enhance drug accumulation at pathological sites. In this study, a novel honokiol nanosuspensions loaded thermosensitive injectable hydrogels (HK-NS-Gel) was designed as the local delivery system for the combination therapy with systemic paclitaxel (PTX). The formed HK-NS-Gel showed superior gelation time and temperature. In vitro release and in vivo drug retention assay showed that HK-NS-Gel can slowly and steadily release the HK during 12 days. Meanwhile, enhanced PTX accumulation in the tumor was observed after intratumoral injection of HK-NS-Gel. In vitro cytotoxicity and cell apoptosis tests against 4T1 cells proved the synergistic effects of free PTX combined with HK-NS-Gel. In vivo antitumor study was conducted on 4T1 bearing mice, indicating that co-administration HK-NS-Gel and PTX could effectively enhance tumor growth suppression, and the tumor inhibitory rate was as high as 72.51%. In conclusion, intravenous delivery of PTX combined with intratumoral delivery of HK-NS-Gel was a promising combination for breast cancer therapy with enhanced therapeutic response and safety.

The potential therapeutic effects of hydroxypropyl cellulose on acute murine colitis induced by DSS.

In this study, high-substituted hydroxypropyl cellulose (HHPC) and low-substituted hydroxypropyl cellulose (LHPC) were orally administered (150 or 300 mg/kg) to investigate the inflammation inhibitory effects on DSS-induced colitis mice. In addition, the anti-inflammatory potential of HHPC in-vitro (RAW 264.7 cells) was evaluated. The result showed that HHPC could inhibit the excessive secretion of TNF-α, IL-6, and NO in RAW 264.7 cells induced by lipopolysaccharide. Oral administration of HHPC and LHPC could dose-dependently mitigate the pathological damage of colon tissue, suppressed spleen edema, preserved thymus index, reduced the serum level of inflammatory mediators (TNF-α, IL-6, IL-1ß, and MPO), increased the secretion of sIgA in the colon, and restored the balance of the intestinal flora such as Rikenellaceae_RC9_gut_group, Lachnospiraceae_UCG-006, and Blautia. Overall, this study elucidated the therapeutic potential of LHPC and HHPC as a prebiotic to treat acute ulcerative colitis.

mPEG-Cholic acid/TPGS mixed micelles for combined delivery of paclitaxel and bufalin to treat hepatocellular carcinoma.

In this study, amphiphilic block copolymer mPEG-cholic acid was synthesized in conjunction with TPGS as stabilizer to prepare multifunctional micelles. The formed polymeric micelles (PCTm) were used for the delivery of paclitaxel (PTX) and bufalin (BF). PEG group could enhance solubility and extend circulation time, while cholic acid groups achieved the liver targeted function. Combinations of these approaches could realize a synergistic therapeutic effect in the treatment of advanced hepatocellular carcinoma. CLSM in vitro results demonstrated that drug capsulation into PCTm could enhance cellular uptake. FCM results confirmed the uptake amount of C6/PCTm was 7.5-fold higher than that of free C6 after incubation for 2 h. Competitive inhibition test proved the Na+-taurocholate co-transporting polypeptide (NTCP) involved in the uptake mechanism of PCTm. Meanwhile, in vivo imaging assays demonstrated that the fluorescence intensity of Cy5.5/PCTm was higher than that of free Cy5.5 on liver and tumor with extended circulation time to 48 h. In addition, in vivo studies confirmed that the combined therapy exhibited the strongest tumor inhibition rate of 82.29% with lower systemic toxicity. Hence, these results indicated that PCTm could provide a promising strategy for targeting hepatocellular carcinoma and achieve the goal of synergism and attenuation.

Combined chemotherapy for triple negative breast cancer treatment by paclitaxel and niclosamide nanocrystals loaded thermosensitive hydrogel.

Triple negative breast cancer (TNBC) is the most dangerous subtype of breast cancer accompanying by unfavorable prognosis due to lack of specific therapeutic targets. Paclitaxel (PTX) is the first-line chemotherapeutic drug for TNBC and niclosamide (NLM) was identified as an inhibitor for TNBC and breast cancer stem cells (BCSCs). Intratumoral drug delivery system was a hopeful alternative for chemotherapeutic drug administration due to its targeting efficiency with lower systemic toxicity. Herein, an injectable PTX nanocrystals (PTX-NCs) and NLM nanocrystals (NLM-NCs) co-loaded PLGA-PEG-PLGA thermosensitive hydrogel (PNNCs-Ts Gel) was designed for TNBC intratumoral treatment. The final formulation realized high drug loading and appropriate particle size. PNNCs-Ts Gel displayed sustained drug release for up to 8 days in vitro. In vitro antitumor tests observed synergetic effects of combined therapy in terms of inhibiting cell proliferation and migration, inducing apoptosis. In vivo combined therapy presented a tumor growth inhibition rate about 68.8% and desired safety. Moreover, tumors after PNNCs-Ts Gel intratumoral injection possessed the lowest ratio of BCSCs, exhibiting this formulation had good ability in suppressing BCSCs and therefore could possibly prevent TNBC recurrence and metastasis. These results suggested that PNNCs-Ts Gel could be a promising strategy for TNBC treatment.

Chitosan/PDLLA-PEG-PDLLA solution preparation by simple stirring and formation into a hydrogel at body temperature for whole wound healing.

Various chitosan (CS)-based dressings are used for wound treatment in clinical settings. Dressings that can be easily prepared and conveniently applied to treat wounds are highly desirable. In this study, a hybrid hydrogel was prepared using CS and poly (D,l-lactide)-poly (ethylene glycol)-poly (D,l-lactide) (PPP) through a simple process for convenient application. The optimal formula included a 7% CS PPP micellar solution, exhibiting excellent liquidity and allowing optional application as a spray. Molecular dynamic simulations indicated that CS and PPP established interactions via H-bonds and formed a long-chain complex, easily forming a hydrogel. Upon application, it rapidly transformed into a hydrogel and tightly adhered to the skin, forming a hemostatic (decreased 53.4%) and antibacterial (increased to about 90%) barrier, demonstrating accelerated wound healing (58.0%). This simple CS hybrid hydrogel can be easily prepared and applied and has potential applicability in clinical wound treatment.

Preparation and evaluation of lecithin/zein hybrid nanoparticles for the oral delivery of Panax notoginseng saponins.

Panax Notoginseng Saponins (PNS) has been widely used in the prevention and treatment of cardiovascular and cerebrovascular diseases such as myocardial infarction, heart failure and cerebral infarction. However, oral administration of PNS showed low bioavailability because of its instability and poor membrane permeability in the gastrointestinal tract. Here, lipoprotein-inspired hybrid nanoparticles of PNS-Lecithin-Zein (PLZ-NPs) were prepared by using a simple phase separation method, which possessed a core-shell structure, where zein was used as protein part to replace the animal origin protein to increase the resistance to acid and enzymes while lecithin was used as the lipid composition to improve the oral absorption of PNS as well as to increase the drug loading capacity of PNS into the nanocarriers. The results of stability test showed that PLZ-NPs had robust enzymolysis resistance ability for acid and digestive enzymes of gastrointestinal environments. The fluorescent resonance energy transfer (FRET) assay confirmed the ability of LZ-NPs to be intactly absorbed by Caco-2 cell monolayer. Cell transport studies demonstrated that the permeability of PLZ-NPs in Caco-2/HT29-MTX co-culture cell model was 1.5-fold that of PNS. Meanwhile, the single-pass intestinal perfusion assay proved the absorption parameter Peff of PLZ-NPs was 1.75 and 1.80 times higher than that of PNS in the ileum and jejunum, respectively. Finally, the in vivo pharmacokinetic experiment showed that the relative oral bioavailability of PLZ-NPs was 1.71-fold that of free PNS in SD rat. In summary, the employment of the Lecithin/Zein hybrid nanoparticles could be considered as a promising approach for PNS analogues.