Milk-derived exosomes as a promising vehicle for oral delivery of hydrophilic biomacromolecule drugs

Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we systematically investigated the effects of drug loading methods and physicochemical properties(lipophilicity and molecular weight)on drug loading efficiency of milk-derived exosomes to explore the most appropriate loading conditions.Our finding revealed that the drug loading efficiency of exosomes was closely related to the drug loading method,drug lipophilicity,drug molecular weight and exosome/drug proportions.Of note,we demonstrated the universality that hydrophilic biomacromolecule drugs were the most appropriate loading drugs for milk-derived exosomes,which was attributed to the efficient loading capacity and sustained release behavior.Furthermore,milk-derived exosomes could significantly improve the transepithelial transport and oral bioavailability of model hydrophilic biomacromolecule drugs(octreotide,exendin-4 and salmon calcitonin).Collectively,our results suggested that the encapsulation of hydrophilic biomacromolecule drugs might be the most promising direction for milk exosomes as oral drug delivery vehicles.

Mimicking natural cholesterol assimilation to elevate the oral delivery of liraglutide for type Ⅱ diabetes therapy

Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are a series of polypeptides broadly applied in the long-term treatment of typeⅡdiabetes.However,administration of GLP-RA is mainly through repetitive subcutaneous injection,which may seriously decrease the compliance and safety.Herein,a bio-inspired oral delivery system was designed to enhance the oral absorption of liraglutide(Lira),a kind of GLP-1 RA,by mimicking the natural cholesterol assimilation.25-hydroxycholesterol(25HC),a cholesterol derivative,was modified on the surfaced of Lira-loaded PLGA nanoparticles(Lira 25HC NPs)and functioned as a“top-down”actuator to facilitate unidirectional transcytosis across the intestinal epithelium.After oral delivery,Lira 25HC NPs displayed improved therapeutic effect as compared with oral free Lira on typeⅡdiabetes db/db mice,as evidenced by multiple relieved diabetic symptoms including the enhanced glucose tolerance,repressed weight growth,improved liver glucose metabolism,decreased fasting blood glucose,HbA 1c,serum lipid,and increasedβcells activity.Surprisingly,the fasting blood glucose,liver glucose metabolism,and HbA1c of oral Lira-loaded 25HC NPs were comparable to subcutaneous injection of free Lira.Further mechanisms revealed that 25HC ligand could mediate the nanoparticles to mimic natural cholesterol absorption by exerting high affinity towards apical Niemann-Pick C1 Like 1(NPC1L1)and then basolateral ATP binding cassette transporter A1(ABCA1)overexpressed on the opposite side of intestinal epithelium.This cholesterol assimilation-mimicking strategy achieve the unidirectional transport across the intestinal epithelium,thus improving the oral absorption of liraglutide.In general,this study established a cholesterol simulated platform and provide promising insight for the oral delivery of GLP-1 RA.

Preparation and Evaluation of Insulin-loaded Nanoparticles based on Hydroxypropyl-β-cyclodextrin Modified Carboxymethyl Chitosan for Oral Delivery

Novel insulin-loaded nanoparticles based on hydroxypropyl-β-cyclodextrin modified carboxymethyl chitosan（CMC-HP-β-CD） were prepared to improve the oral bioavailability of insulin. The CMC-HP-β-CD was characterized by FT-IR spectroscopy and 1H-NMR spectra. The insulin-loaded nanoparticles were prepared through crosslinking with calcium ions, and the morphology and size of the prepared nanoparticles were characterized by transmission electron microscopy（TEM） and dynamic light scattering（DLS）. Cumulative release in vitro study was performed respectively in simulated gastric medium fluid（SGF, p H=1.2）, simulated intestinal fluid（SIF, p H=6.8） and simulated colonic fluid（SCF, p H=7.4）. The encapsulation efficiency of insulin was up to 87.14 ± 4.32% through high-performance liquid chromatography（HPLC）. Statistics indicated that only 15% of the encapsulated insulin was released from the CMC-HP-β-CD nanoparticles in 36 h in SGF, and about 50% of the insulin could be released from the nanoparticles in SIF, whereas more than 80% was released in SCF. In addition, the solution containing insulin nanoparticles could effectively reduce the blood glucose level of diabetic mice. The cytotoxicity test showed that the samples had no cytotoxicity. CMC-HP-β-CD nanoparticles are promising candidates as potential carriers in oral insulin delivery systems.

Oral delivery of ferroptosis inducers for effective treatment of hepatic fibrosis

Liver fibrosis is characterized by the excessive accumulation of extracellular matrix(ECM),which is primarily produced by activated hepatic stellate cells(HSCs).However,effective therapies for hepatic fibrosis are currently lacking.Artesunate is a promising anti-fibrotic drug candidate,but its clinical application is hindered by limited absorption.Here,we present a novel oral delivery platform that enhances the HSCs uptake of artesunate and induces potent ferroptosis.The platform is vitamin Adecorated nanoparticles encapsulated with artesunate.The multifunctional ligand vitamin A interacts with retinol-binding proteins that are highly expressed on the intestinal epithelium to promote transcytosis,highly expressed on the surface of HSCs but lowly expressed in normal hepatocytes.After oral administration,this oral delivery platform enhances transepithelial transport in the intestine,improves drug accumulation in the liver,and continuously increases HSCs uptake of artesunate.Upon drug release in HSCs,artesunate depletes glutathione peroxidase 4 and glutathione,effectively initiating ferroptosis.In vivo experiments demonstrate that this strategy induces pronounced ferroptosis,efficiently relieving liver fibrosis.This work provides a proof-ofconcept demonstration that an oral delivery strategy for ferroptosis inducers may be beneficial for liver fibrosis treatment.

Mesoporous silica nanoparticles with chiral pattern topological structure function as“antiskid tires”on the intestinal mucosa to facilitate oral drugs delivery

The weak adhesion between nanocarriers and the intestinal mucosa was one of the main reasons caused the failure in oral delivery.Inspired by the“antiskid tires”with complex chiral patterns,mesoporous silica nanoparticles AT-R@CMSN exhibiting geometrical chiral structure were designed to improve the surface/interface roughness in nanoscale,and employed as the hosting system for insoluble drugs nimesulide(NMS)and ibuprofen(IBU).Once performing the delivery tasks,AT-R@CMSN with rigid skeleton protected the loaded drug and reduced the irritation of drug on gastrointestinal tract(GIT),while their porous structure deprived drug crystal and improved drug release.More importantly,AT-R@CMSN functioned as“antiskid tire”to produce higher friction on intestinal mucosa and substantively influencedmultiple biological processes,including“contact”,“adhesion”,“retention”,“permeation”and“uptake”,compared to the achiral S@MSN,thereby improving the oral adsorption effectiveness of such drug delivery systems.By engineering AT-R@CMSN to overcome the stability,solubility and permeability bottlenecks of drugs,orally administered NMS or IBU loaded AT-R@CMSN could achieve higher relative bioavailability(705.95%and 444.42%,respectively)and stronger anti-inflammation effect.In addition,AT-R@CMSN displayed favorable biocompatibility and biodegradability.Undoubtedly,the present finding helped to understand the oral adsorption process of nanocarriers,and provided novel insights into the rational design of nanocarriers.

Alginate-coated quaternized chitosan nanoparticles for oral delivery of insulin

In the present work, we aimed to develop alginate-coated chitosan nanoparticles for oral insulin delivery. The N-[（2-hydroxy- 3-trimethylammonium）propyl] chitosan chloride （HTCC） was synthesized, and the quatemized chitosan nanoparticles （HTCC-T NPs） were prepared by ionic gelation of HTCC using tripolyphosphate （TPP）. The alginate-coated quatemized chitosan nanoparticles （HTCC-A NPs） were prepared by coating HTCC-T NPs with alginate （ALG） solution under mild agitation. Particle size, zeta potential, surface morphology, drug loading and entrapment efficiency of HTCC-A NPs were characterized using Zeta-sizer, TEM and HPLC assays. It was found that HTCC-A NPs exhibited uniform spherical particles with the size of （322.2±8.5） nm and positive charges （14.1±0.6） mV. Our data showed that the release behavior of HTCC-A NPs was quite different from that of HTCC-T NPs （without ALG coating） when incubated with various medium at different pH values in vitro, suggesting that ALG coating over the HTCC-T NPs improved the release profile of insulin from the NPs for a successful oral delivery. The ALG coating could also improve the stability of insulin against enzymatic degradation. From circular dichroism spectrum, it was revealed that HTCC-A NPs were capable of maintaining the conformation of insulin. The relative pharmacological bioavailability of HTCC-A NPs was 8.0%±2.5% by intraduodenal administration. The HTCC-A NPs significantly increased （P〈0.05） the relative pharmacological availability （2.2 folds） compared with HTCC-T NPs after oral administration. HTCC-A NPs significantly enhanced the in vivo oral absorption of insulin and exhibited promising potentials for oral delivery.

Oral delivery of proteins and peptides:Challenges, status quo and future perspectives

Proteins and peptides(PPs)have gradually become more attractive therapeutic molecules than small molecular drugs due to their high selectivity and efficacy,but fewer side effects.Owing to the poor stability and limited permeability through gastrointestinal(GI)tract and epithelia,the therapeutic PPs are usually administered by parenteral route.Given the big demand for oral administration in clinical use,a variety of researches focused on developing new technologies to overcome GI barriers of PPs,such as enteric coating,enzyme inhibitors,permeation enhancers,nanoparticles,as well as intestinal microdevices.Some new technologies have been developed under clinical trials and even on the market.This review summarizes the history,the physiological barriers and the overcoming approaches,current clinical and preclinical technologies,and future prospects of oral delivery of PPs.

Compartmentalized Metabolic Engineering for Artemisinin Biosynthesis and Effective Malaria Treatment by Oral Delivery of Plant Cells

Artemisinin is highly effective against drug-resistant malarial parasites, which affects nearly half of the global population and kills 〉500 000 people each year. The primary cost of artemisinin is the very expensive process used to extract and purify the drug from Artemisia annua. Elimination of this apparently unnecessary step will make this potent antimalarial drug affordable to the global population living in endemic regions. Here we reported the oral delivery of a non-protein drug artemisinin biosynthesized （~0.8 mg/g dry weight） at clinically meaningful levels in tobacco by engineering two metabolic pathways targeted to three different cellular compartments （chloroplast, nucleus, and mitochondria）. The doubly transgenic lines showed a three-fold enhancement of isopentenyl pyrophosphate, and targeting AACPR, DBR2, and CYP71AV1 to chloroplasts resulted in higher expression and an efficient photo-oxidation of di- hydroartemisinic acid to artemisinin. Partially purified extracts from the leaves of transgenic tobacco plants inhibited in vitro growth progression of Plasmodium falciparum-infected red blood cells. Oral feeding of whole intact plant cells bioencapsulating the artemisinin reduced the parasitemia levels in challenged mice in comparison with commercial drug. Such novel synergistic approaches should facilitate low-cost production and delivery of artemisinin and other drugs through metabolic engineering of edible plants.

Homogeneous PLGA-lipid nanoparticle as a promising oral vaccine delivery system for ovalbumin

In this study,a polymeric lipid nanoparticle(NP)(simplified as Lipid NP)was reported as a promising oral vaccine delivery system.The Lipid NPs composed of a hydrophobic polymeric poly(D,L-lactide-co-glycolide)(PLGA)core and a surface coating of lipid monolayer.Membrane emulsification technique was used to obtain uniform-sized Lipid NPs.Ovalbumin(OVA)was used as a model vaccine.Compared with the pure PLGA NPs,the Lipid NPs achieved higher loading capacity(LC)and entrapment efficiency(EE)for the encapsulated OVA.An in vitro oral release profile showed that the OVA-Lipid NPs were with lower initial burst and could protect the loaded OVA from the harsh gastrointestinal(GI)environment for a long time.In addition,a human microfold cell(M-cell)transcytotic assay demonstrated that due to a lipid layer structure on the particle surface,the Lipid NPs showed higher affinity to the M-cells.Since the M-cell in the intestinal epithelium played an important role in particle transportation as well as intimately associated with the underlying immune cells,the OVA-Lipid NPs effectively induced mucosal and humoral immune responses.

Fabrication strategies and supramolecular interactions of polymer-lipid complex nanoparticles as oral delivery systems

Oral administration of nutrient/drug is the most common and preferred route. However, a number of barriers are encountered after ingestion, limiting efficient oral nutrient/drug absorption. Both lipid-based (e.g., nanoemulsion, solid lipid nanoparticles) and polymer-based (e.g., protein and polysaccharide nanoparticles) nanoscale delivery systems have demonstrated capability to overcome some of these physiological barriers during transportation and metabolism stages. To better deal with those barriers, polymer-lipid complex nanoparticles are being explored and developed to merge the beneficial features and overcome the respective shortcomings of lipid-based and polymer-based nanoparticles. This paper aims to provide an overview of the various preparation strategies and supramolecular interactions of orally administered polymer-lipid complex nanoparticles by reviewing recent studies. Two types of polymer-lipid complex nanoparticles have been developed, i.e., lipid core with polymer shell nanoparticles and polymer core with lipid shell nanoparticles (lipid-polymer hybrid nanoparticles). Besides, both natural and synthetic polymers used for fabrication are discussed and their advantages and disadvantages are highlighted. Further research work is needed to optimize the fabrication and scaling up processes, so that these versatile polymer-lipid complex nanoparticles could have a significant impact on the oral delivery of nutrient/drug.

Proton-Resistant Quantum Dots: Stability in Gastrointestinal Fluids and Implications for Oral Delivery of Nanoparticle Agents

Semiconductor quantum dots(QDs)have shown great promise as fluorescent probes for molecular,cellular and in vivo imaging.However,the fluorescence of traditional polymer-encapsulated QDs is often quenched by proton-induced etching in acidic environments.This is a major problem for applications of QDs in the gastrointestinal tract because the gastric(stomach)environment is strongly acidic(pH 12).Here we report the use of proton-resistant surface coatings to stabilize QD fl uorescence under acidic conditions.Using both hyperbranched polyethylenimine(PEI)and its polyethylene glycol derivative(PEG-grafted PEI),we show that the fl uorescence of coreshell CdSe/CdS/ZnS QDs is effectively protected from quenching in simulated gastric fluids.In comparison,amphiphilic lipid or polymer coatings provide no protection under similarly acidic conditions.The proton-resistant QDs are found to cause moderate membrane damage to cultured epithelial cells,but PEGylation(PEG grafting)can be used to reduce cellular toxicity and to improve nanoparticle stability.

Intestine Enzyme-responsive Polysaccharide-based Hydrogel to Open Epithelial Tight Junctions for Oral Delivery of Imatinib against Colon Cancer

Imatinib has been widely used as a selective kinase inhibitor for treating a variety of cancers,and this molecule is very hydrophobic so it is usually modified with mesylate salt in clinic to increase bioavailability.However,pH-dependent aqueous solubility and relatively high dosage of imatinib mesylate greatly reduce the clinical outcomes.To solve this problem,we developed an intestine enzyme-responsive hydrogel to efficiently encapsulate hydrophobic imatinib with long-term controlled release and enhanced intestinal permeability through oral administration.Methacrylic anhydride-modified carboxymethyl chitosan(MA-CMCS)was synthesized via amidation reaction and then MA-CMCS was crosslinked with photoinitator under UV-irradation to form a three-dimensional hydrophilic polymer network.The intestine enzyme responsiveness was endowed with imatinib-loaded hydrogel through hydrolyzation of glucosidic bond,which could achieve enzyme-triggered long-term drug release of up to 2 days.Furthermore,sodium deoxycholate was embedded into the hydrogel to synchronously open epithelial tight junctions with improved intestinal permeability.In vitro studies revealed similar lethality against colon cancer cell for both imatinib mesylate and imatinib-loaded hydrogels.Moreover,significantly enhanced in vivo tumor inhibition(6-fold higher compared to imatinib mesylate)was achieved after oral administration with imatinib-loaded hydrogels.Overall,this enzyme-responsive hydrogel could achieve long-term synchronous release of kinase inhibitor(imatinib)and tight junction permeation enhancer(sodium deoxycholate)at intestine with enhanced therapeutic efficiency,which could provide an effective approach to improve the bioavailability of hydrophobic anticancer chemodrugs with oral administration.

Advanced delivery strategies facilitating oral absorption of heparins

Heparins show great anticoagulant effect with few side effects,and are administered by subcutaneous or intravenous route in clinics.To improve patient compliance,oral administration is an alternative route.Nonetheless,oral administration of heparins still faces enormous challenges due to the multiple obstacles.This review briefly analyzes a series of barriers ranging from poorly physicochemical properties of heparins,to harsh biological barriers including gastrointestinal degradation and pre-systemic metabolism.Moreover,several approaches have been developed to overcome these obstacles,such as improving stability of heparins in the gastrointestinal tract,enhancing the intestinal epithelia permeability and facilitating lymphatic delivery of heparins.Overall,this review aims to provide insights concerning advanced delivery strategies facilitating oral absorption of heparins.

Micro-ecology restoration of colonic inflammation by in-Situ oral delivery of antibody-laden hydrogel microcapsules

In-situ oral delivery of therapeutic antibodies,like monoclonal antibody,for chronic inflammation treatment is the most convenient approach compared with other administration routes.Moreover,the abundant links between the gut microbiota and colonic inflammation indicate that the synergistic or antagonistic effect of gut microbiota to colonic inflammation.However,the antibody activity would be significantly affected while transferring through the gastrointestinal tract due to hostile conditions.Moreover,these antibodies have short serum half-lives,thus,require to be frequently administered with high doses to be effective,leading to low patient tolerance.Here,we develop a strategy utilizing thin shell hydrogel microcapsule fabricated by microfluidic technique as the oral delivering carrier.By encapsulating antibodies in these microcapsules,antibodies survive in the hostile gastrointestinal environment and rapidly release into the small intestine through oral administration route,achieving the same therapeutic effect as the intravenous injection evaluated by a colonic inflammation disease model.Moreover,the abundance of some intestinal microorganisms as the indication of the improvement of inflammation has remarkably altered after in-situ antibody-laden microcapsules delivery,implying the restoration of micro-ecology of the intestine.These findings prove our microcapsules are exploited as an efficient oral delivery agent for antibodies with programmable function in clinical application.

Gut lumen-targeted oral delivery system for bioactive agents to regulate gut microbiome

Gut microbiome(GM)is closely related to the overall health status for the human being.The dysfunction of microbiome can lead to many diseases such as inflammation,cancer and neurodegenerative disease.Therefore,it's of great importance to develop effective strategy to regulate GM.Gut lumen-targeted oral delivery system(GLT-ODS)has been extensively investigated and widely used in food science and engineering in these years,due to the targeted delivery property,controlled release profile,high biocompatibility and enhanced bioavailability of cargos.Herein,we comprehensively summarized the current advances in GLT-ODS for bioactive agent.Specifically,we systematically summarize the GLT-ODS for pre-agents(prebiotics and probiotics)and anti-agents(antibiotics and bacteriophages)according to the type of cargos.Through in-depth discussion of representative researches,we refined the limitations of existing research in carrier material and target selection,and drew a blueprint for the future technological research and development.We believe that GLT-ODS will become a safe,efficient,simple and precise GM management strategy for improvement of health and shine in the development of precision food and pharmaceutical engineering in future.

The complexation of insulin with sodium N-[8-(2-hydroxybenzoyl)amino]-caprylate for enhanced oral delivery:Effects of concentration, ratio, and pH

Permeation enhancers(PEs),such as N-[8-(2-hydroxybenzoyl)amino]-caprylate(SNAC),have been reported to improve the oral absorption of various macromolecules.However,the bioavailabilities of these formulations are quite low and variable due to the influences of enzymes,pH and other gastrointestinal barriers.In this study,we revealed that SNAC could interact with insulin to form tight complexes in a specific concentration(insulin≥ 40μg/mL)-,ratio(SNAC/insulin≥ 20:1)-and pH(≥ 6.8)-dependent manner,thus contributing to a significantly high efficacy of oral insulin delivery.Specifically,absorption mechanism studies revealed that the SNAC/insulin complexes were internalized into the cells by passive diffusion and remained intact when transported in the cytosol.Furthermore,the complexes accelerated the exocytosis of insulin to the basolateral side,thereby enhancing its intestinal mucosal permeability.Eudragit;S100-entrapped SNAC/insulin microspheres were then prepared and exhibited an apparent permeability coefficient(P;) that was 6,6-fold higher than that of the insulin solution.In diabetic rats,hypoglycemic activity was sustained for more than 10 h after the microspheres were loaded into entericcoated capsules.Further pharmacokinetic studies revealed an approximately 6.3% oral bioavailability in both the fasted and fed states,indicating a negligible food effect.Collectively,this study provides insight into the interaction between PEs and payloads and presents an SNAC-based oral insulin delivery system that has high oral bioavailability and patient-friendly medication guidance.

UNIQUE ORAL DRUG DELIVERY SYSTEM

An oral drug delivery system using proteinoid microspheres is discussed with respect to itsunique dependence on pH. It has been found that certain drugs such as insulin and heparin canbe encapsulated in proteinoid spheres at stomach pH's (1--3). These spheres also dissemble atintestinal pH's (6--7) releasing the drug for absorption. Using this technique low molecularweight heparin and human growth hormone have been orally delivered successfully to severalanimal species. Future work has been proposed to study the interaction and binding of thespecific drugs with synthesized oligopeptides.

Chitosan DNA nanoparticles for oral gene delivery

Gene therapy is a promising technology with potential applications in the treatment of medical conditions, both congenital and acquired. Despite its label as breakthrough technology for the 21st century, the simple concept of gene therapy - the introduction of a functional copy of desired genes in affected individuals - is proving to be more challenging than expected. Oral gene delivery has shown intriguing results and warrants further exploration. In particular, oral administration of chitosan DNA nano-particles, one the most commonly used formulations of therapeutic DNA, has repeatedly demonstrated successful in vitro and in vivo gene transfection. While oral gene therapy has shown immense promise as treatment options in a variety of diseases, there are still signifcant barriers to overcome before it can be considered for clinical applications. In this review we provide an over-view of the physiologic challenges facing the use of chitosan DNA nanoparticles for oral gene delivery at both the extracellular and intracellular level. From administration at the oral cavity, chitosan nanoparticles must traverse the gastrointestinal tract and protect its DNA contents from signifcant jumps in pH levels, various intestinal digestive enzymes, thick mucus layers with high turnover, and a proteinaceous glycocalyx meshwork. Once these extracellular barriers are overcome, chitosan DNA nanoparticles must enter intestinal cells, escape endolysosomes, and disassociate from genetic material at the appropriate time allowing transport of genetic material into the nucleus to deliver a therapeutic ef-fect. The properties of chitosan nanoparticles and modified nanoparticles are discussed in this review. An understanding of the barriers to oral gene delivery and how to overcome them would be invaluable for future gene therapy development.

一种双层多糖水凝胶用于增强益生菌肠道靶向口服递送

Transplantation of probiotics to the intestine can positively regulate the gut microbiota,thereby promoting the immune system and treating various diseases.However,the harsh gastrointestinal environment and short retention time in the gastrointestinal tract significantly limit the bioavailability and intestinal colonization of probiotics.Herein,we present a double-layer polysaccharide hydrogel(DPH)in the form of a double-layer structure composed of a carboxymethyl cellulose(CMCL)supramolecular inner layer and a dialdehyde alginate(DAA)cross-linked carboxymethyl chitosan(CMCS)outer layer.This doublelayer structure allows DPH to encapsulate and deliver probiotics in a targeted manner within the body.In the stomach,the cage structure of the DPH is closed,and the outer layer absorbs surrounding liquids to form a barrier to protect the probiotics from gastric fluids.In the intestine,the cage structure opens and disintegrates,releasing the probiotics.Thus,DPH endows probiotics with excellent intestine-targeted delivery,improved oral bioavailability,enhanced gastrointestinal tract tolerance,and robust mucoadhesion capacity.The encapsulated probiotics exhibit almost unchanged bioactivity in the gastrointestinal tract before release,as well as improved oral delivery.In particular,probiotics encapsulated by DPH exhibit 100.1 times higher bioavailability and 10.6 times higher mucoadhesion than free probiotics in an animal model 48 h post-treatment.In addition,with a remarkable ability to survive and be retained in the intestine,probiotics encapsulated by DPH show excellent in vitro and in vivo competition with pathogens.Notably,DAA-mediated dynamic crosslinking not only maintains the overall integrity of the hydrogels but also controls the release timing of the probiotics.Thus,it is expected that encapsulated substances(probiotics,proteins,etc.)can be delivered to specific sites of the intestinal tract by means of DPH,by controlling the dynamic covalent crosslinking.

Transepithelial transport of nanoparticles in oral drug delivery:From the perspective of surface and holistic property modulation

Despite the promising prospects of nanoparticles in oral drug delivery,the process of oral administration involves a complex transportation pathway that includes cellular uptake,intracellular trafficking,and exocytosis by intestinal epithelial cells,which are necessary steps for nanoparticles to enter the bloodstream and exert therapeutic effects.Current researchers have identified several crucial factors that regulate the interaction between nanoparticles and intestinal epithelial cells,including surface properties such as ligand modification,surface charge,hydrophilicity/hydrophobicity,intestinal protein corona formation,as well as holistic properties like particle size,shape,and rigidity.Understanding these properties is essential for enhancing transepithelial transport efficiency and designing effective oral drug delivery systems.Therefore,this review provides a comprehensive overview of the surface and holistic properties that influence the transepithelial transport of nanoparticles,elucidating the underlying principles governing their impact on transepithelial transport.The review also outlines the chosen of parameters to be considered for the subsequent design of oral drug delivery systems.