Atherosclerosis (AS) is a serious disease that poses a significant threat to the global population. In this review, we analyze the development of AS from multiple perspectives, aiming to elucidate its molecular mechanisms. We also focus on imaging techniques and therapeutic approaches, highlighting the crucial role of nanomaterials in both imaging and therapy for AS. By leveraging their compatibility and targeting capabilities, nanomaterials can be integrated with traditional medical imaging and therapeutic agents to achieve targeted drug delivery, controlled release, and precise localization and imaging of atherosclerotic plaques.

Modulating the endogenous stores of gastrointestinal hormones is considered a promising strategy to mimic gut endocrine function, improving metabolic dysfunction. Here, we exploit mouse and human knock-in and knockout intestinal organoids and show that agents used as commercial lipid excipients can activate nutrient-sensitive receptors on enteroendocrine cells (EECs) and, when formulated as lipid nanocarriers, can bestow biological effects through the release of GLP-1, GIP, and PYY from K and L cells. Studies in wild-type, dysglycemic, and gut Gcg knockout mice demonstrated that the effect exerted by lipid nanocarriers could be modulated by varying the excipients (e.g., nature and quantities), the formulation methodology, and their physiochemical properties (e.g., size and composition). This study demonstrates the therapeutic potential of using nanotechnology to modulate release of multiple endogenous hormones from the enteroendocrine system through a patient-friendly, inexpensive, and noninvasive manner.

Several nanotechnology-based formulation strategies have been reported for the oral administration of biological drugs. However, a prerequisite often overlooked in developing these formulations is their adaptation to a solid dosage form. This study aimed to incorporate a freeze-drying step, using either mannitol or sucrose laurate (SLAE), into the formulation of new insulin-zinc nanocomplexes to render them resistant to intestinal fluids while maintaining a high protein loading. The resulting freeze-dried insulin-zinc nanocomplexes exhibited physicochemical properties consistent with the target product profile, including a particle size of ∼ 100 nm, a zeta potential close to neutrality (∼ -15 mV) and a high association efficiency (> 90%). Importantly, integrating the freeze-drying step in the formulation significantly improved the colloidal stability of the system and preserved the stability of the insulin molecules. Results from in vitro and in vivo studies indicated that the insulin activity remained fully retained throughout the entire formulation and freeze-drying processes. In brief, we present a novel protein formulation strategy that incorporates a critical freeze-drying step, resulting in a dry powder enabling efficient protein complexation with zinc and optimized for oral administration.

Nanosecond pulsed laser induced photoporation has gained increasing attention from scholars as an effective method for delivering the membrane-impermeable extracellular materials into living cells. Compared with femtosecond laser, nanosecond laser has the advantage of high throughput and low costs. It also has a higher delivery efficiency than continuous wave laser. Here, we provide an extensive overview of current status of nanosecond pulsed laser induced photoporation, covering the photoporation mechanism as well as various factors that impact the delivery efficiency of photoporation. Additionally, we discuss various techniques for achieving photoporation, such as direct photoporation, nanoparticles-mediated photoporation and plasmonic substrates mediated photoporation. Among these techniques, nanoparticles-mediated photoporation is the most promising approach for potential clinical application. Studies have already been reported to safely destruct the vitreous opacities in vivo by nanosecond laser induced vapor nanobubble. Finally, we discuss the potential of nanosecond laser induced phototoporation for future clinical applications, particularly in the areas of skin and ophthalmic pathologies. We hope this review can inspire scientists to further improve nanosecond laser induced photoporation and facilitate its eventual clinical application.

The oral administration of the glucagon-like peptide-1 analogue, semaglutide, remains a hurdle due to its limited bioavailability. Herein, neonatal Fc receptor (FcRn)-targeted nanoparticles (NPs) were designed to enhance the oral delivery of semaglutide. The nanocarriers were covalently linked to the FcRn-binding peptide FcBP or the affibody molecule ZFcRn that specifically binds to the human FcRn (hFcRn) in a pH-dependent manner. These FcRn-targeted ligands were selected over the endogenous ligands of the receptor (albumin and IgG) due to their smaller size and simpler structure, which could facilitate the transport of functionalized NPs through the tissues. The capacity of FcRn-targeted semaglutide-NPs in controlling the blood glucose levels was evaluated in an hFcRn transgenic mice model, where type 2 diabetes mellitus (T2DM) was induced via intraperitoneal injection of nicotinamide followed by streptozotocin. The encapsulation of semaglutide into FcRn-targeted NPs was translated in an improved glucoregulatory effect in T2DM-induced mice when compared to the oral free semaglutide or nontargeted NP groups, after daily oral administrations for 7 days. Notably, a similar glucose-lowering response was observed between both FcRn-targeted NPs and the subcutaneous semaglutide groups. An increase in insulin pancreatic content and a recovery in β cell mass were visualized in the mice treated with FcRn-targeted semaglutide-NPs. The biodistribution of fluorescently labeled NPs through the gastrointestinal tract demonstrated that the nanosystems targeting the hFcRn are retained longer in the ileum and colorectum, where the expression of FcRn is more prevalent, than nontargeted NPs. Therefore, FcRn-targeted nanocarriers proved to be an effective platform for improving the pharmacological effect of semaglutide in a T2DM-induced mice model.

In this contribution to the Orations - New Horizons of the Journal of Controlled Release, I discuss the research that we have conducted on gut hormone stimulation as a therapeutic strategy in oral peptide delivery. One of the greatest challenges in oral drug delivery involves the development of new drug delivery systems that enable the absorption of therapeutic peptides into the systemic circulation at therapeutically relevant concentrations. This scenario is especially challenging in the treatment of chronic diseases (such as type 2 diabetes mellitus), wherein daily injections are often needed. However, for certain peptides, there may be an alternative in drug delivery to meet the need for increased peptide bioavailability; this is the case for gut hormone mimetics (including glucagon-like peptide (GLP)-1 or GLP-2). One plausible alternative for improved oral delivery of these peptides is the co-stimulation of the endogenous secretion of the hormone to reach therapeutic levels of the peptide. This oration will be focused on studies conducted on the stimulation of gut hormones secreted from enteroendocrine L cells in the treatment of gastrointestinal disorders, including a critical discussion of the limitations and future perspectives of implementing this approach in the clinical setting.

Food-related functional substances with biological activity serve as a crucial material foundation for achieving precision nutrition, which has gained increasing attraction in regulating physiological functions, preventing chronic diseases, and maintaining human health. Nutritional substances typically include bioactive proteins, peptides, polysaccharides, polyphenols, functional lipids, carotenoids, probiotics, vitamins, saponins, and terpenes. These functional substances play an essential role in precise nutrition. This chapter introduces and summarizes typical functional substances to demonstrate the challenges in precision nutrition for their stability, solubility, and bioavailability. The current status of delivery systems of functional substances is described to give an insight into the development of desirable characteristics, such as food grade status, high loading capacity, site targeting, and controlled release capacity. Finally, the applications of food-borne delivery systems of functional substances for precision nutrition are emphasized to meet the requirement for precision nutrition during nutritional intervention for chronic diseases.

Diabetes, characterized by hyperglycemia, is a major cause of death and disability worldwide. Peptides, such as insulin and glucagon-like peptide-1 (GLP-1) analogs, have shown promise as treatments for diabetes due to their ability to mimic or enhance insulin's actions in the body. Compared to subcutaneous injection, oral administration of anti-diabetic peptides is a preferred approach. However, biological barriers significantly reduce the efficacy of oral peptide therapeutics. Recent advancements in drug delivery systems and formulation techniques have greatly improved the oral delivery of peptide therapeutics and their efficacy in treating diabetes. This review will highlight (1) the benefits of oral anti-diabetic peptide therapeutics; (2) the biological barriers for oral peptide delivery, including pH and enzyme degradation, intestinal mucosa barrier, and biodistribution barrier; (3) the delivery platforms to overcome these biological barriers. Additionally, the review will discuss the prospects in this field. The information provided in this review will serve as a valuable guide for future developments in oral anti-diabetic peptide therapeutics.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that arises when the body cannot respond fully to insulin, leading to impaired glucose tolerance. Currently, the treatment embraces non-pharmacological actions (e.g., diet and exercise) co-associated with the administration of antidiabetic drugs. Metformin is the first-line treatment for T2DM; nevertheless, alternative therapeutic strategies involving glucagon-like peptide-1 (GLP-1) analogs have been explored for managing the disease. GLP-1 analogs trigger insulin secretion and suppress glucagon release in a glucose-dependent manner thereby, reducing the risk of hyperglycemia. Additionally, GLP-1 analogs have an extended plasma half-life compared to the endogenous peptide due to their high resistance to degradation by dipeptidyl peptidase-4. However, GLP-1 analogs are mainly administered via subcutaneous route, which can be inconvenient for the patients. Even considering an oral delivery approach, GLP-1 analogs are exposed to the harsh conditions of the gastrointestinal tract (GIT) and the intestinal barriers (mucus and epithelium). Hereupon, there is an unmet need to develop non-invasive oral transmucosal drug delivery strategies, such as the incorporation of GLP-1 analogs into nanoplatforms, to overcome the GIT barriers. Nanotechnology has the potential to shield antidiabetic peptides against the acidic pH and enzymatic activity of the stomach. In addition, the nanoparticles can be coated and/or surface-conjugated with mucodiffusive polymers and target intestinal ligands to improve their transport through the intestinal mucus and epithelium. This review focuses on the main hurdles associated with the oral administration of GLP-1 and GLP-1 analogs, and the nanosystems developed to improve the oral bioavailability of the antidiabetic peptides. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Current treatments for inflammatory bowel disease (IBD) treatment consist of anti-inflammatory products. In this study, we sought to induce the physiological secretion of glucagon-like peptide 2, a peptide with intestinal growth-promoting activity, via nanoparticles while simultaneously providing with immunomodulation by tailoring the nanoparticle surface. To this end, we developed hybrid lipid hyaluronate-KPV conjugated nanoparticles loaded with teduglutide for combination therapy in IBD. The nanocarriers induced (or did not induce) immunosuppression depending on the presence (or absence) of a hyaluronan-KPV functionalization. This strategy holds promise as a nanoparticle platform for combined mucosal healing and immunomodulation in IBD treatment.

Although colloidal carriers have been in the pipeline for nearly four decades, standardized methods for testing their drug-release properties remain to be established in pharmacopeias. The in vitro assessment of drug release from these colloidal carriers is one of the most important parameters in the development and quality control of drug-loaded nano- and microcarriers. This lack of standardized protocols occurs due to the difficulties encountered in separating the released drug from the encapsulated one. This review aims to compare the most frequent types of release testing methods (i.e., membrane diffusion techniques, sample and separate methods and in situ detection techniques) in terms of the advantages and disadvantages of each one and of the key parameters that influence drug release in each case.

Oral administration is the preferred route of administration based on the convenience for and compliance of the patient. Oral nanomedicines have been developed to overcome the limitations of free drugs and overcome gastrointestinal (GI) barriers, which are heterogeneous across healthy and diseased populations. This review aims to provide a comprehensive overview and comparison of the oral nanomedicine biointeractions in the gastrointestinal tract (GIT) in health and disease (GI and extra-GI diseases) and highlight emerging strategies that exploit these differences for oral nanomedicine-based treatment. We introduce the key GI barriers related to oral delivery and summarize their pathological changes in various diseases. We discuss nanomedicine biointeractions in the GIT in health by describing the general biointeractions based on the type of oral nanomedicine and advanced biointeractions facilitated by advanced strategies applied in this field. We then discuss nanomedicine biointeractions in different diseases and explore how pathological characteristics have been harnessed to advance the development of oral nanomedicine.

The oral absorption of exenatide, a type 2 diabetes medication, can be increased by employing lipid nanocapsules (LNC). To increase mucus permeability and exenatide intestinal absorption, reverse micelle lipid nanocapsules (RM-LNC) were prepared and their surface was modified with DSPE-PEG-FA. The RM-LNC with surface modification of DSPE-PEG-FA (FA-RM-LNC) were able to target enterocytes and reduce mucus aggregation in the intestine. Furthermore, in vitro absorption at different intestinal sites and flip-flop intestinal loop experiments revealed that LNCs with surface modification significantly increased their absorption efficiency in the small intestine. FA-RM-LNC delivers more drugs into Caco-2 cells via caveolin-, macrophagocytosis-, and lipid raft-mediated endocytosis. Additionally, the enhanced transport capacity of FA-RM-LNC was observed in a study of monolayer transport in Caco-2 cells. The oral administration of exenatide FA-RM-LNC resulted in a prolonged duration of hypoglycemia in diabetic mice and a relative bioavailability (BR) of up to 7.5% in rats. In conclusion, FA-RM-LNC can target enterocytes and has promising potential as a nanocarrier for the oral delivery of peptides.

G protein-coupled receptors (GPCRs), as the largest family of membrane receptors, actively modulate plasma membrane and endosomal signalling. Importantly, GPCRs are naturally nanosized, and spontaneously formed nanoaggregates of GPCRs (natural nano-GPCRs) may enhance GPCR-related signalling and functions. Although GPCRs are the molecular targets of the majority of marketed drugs, the poor pharmacokinetics and physicochemical properties of GPCR ligands greatly limit their clinical applicability. Nanotechnology, as versatile techniques, can encapsulate GPCR ligands to assemble synthetic nano-GPCRs to overcome their obstacles, robustly elevating drug efficacy and safety. Moreover, endosomal delivery of GPCR ligands by nanoparticles can precisely initiate sustained endosomal signal transduction, while nanotechnology has been widely utilized for isolation, diagnosis, and detection of GPCRs. In turn, due to overexpression of GPCRs on the surface of various types of cells, GPCR ligands can endow nanoparticles with active targeting capacity for specific cells via ligand-receptor binding and mediate receptor-dependent endocytosis of nanoparticles. This significantly enhances the potency of nanoparticle delivery systems. Therefore, emerging evidence has revealed the interplay between GPCRs and nanoparticles, although investigations into their relationship have been inadequate. This review aims to summarize the interaction between GPCRs and nanotechnology for understanding their mutual influences and utilizing their interplay for biomedical applications. It will provide a fundamental platform for developing powerful and safe GPCR-targeted drugs and nanoparticle systems. STATEMENT OF SIGNIFICANCE: GPCRs as molecular targets for the majority of marketed drugs are naturally nanosized, and even spontaneously form nano aggregations (nano-GPCRs). Nanotechnology has also been applied to construct synthetic nano-GPCRs or detect GPCRs, while endosomal delivery of GPCR ligands by nanoparticles can magnify endosomal signalling. Meanwhile, molecular engineering of nanoparticles with GPCRs or their ligands can modulate membrane binding and endocytosis, powerfully improving the efficacy of nanoparticle system. However, there are rare summaries on the interaction between GPCRs and nanoparticles. This review will not only provide a versatile platform for utilizing nanoparticles to modulate or detect GPCRs, but also facilitate better understanding of the designated value of GPCRs for molecular engineering of biomaterials with GPCRs in therapeutical application.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder, which is ultimately treated by the insulin (INS). However, the subcutaneous (s. c.) injection of insulin solution faces the problems of pain and unsatisfactory patient compliance. In this study, the long-acting formulations of insulin are propsed to treat the T2DM and prevent the associated complications. The chitosan (CS) and/or branched polyethyleneimine (bPEI) nanoparticles (bPEI-INS NPs, CS-bPEI-INS NPs) were constructed to load insulin. The long -acting nanoparticles successfully achieved the sustained release of the INS in vitro and in vivo. After s. c. administration, the CS-bPEI-INS NPs greatly improved the INS bioavailability. As a result, the CS-bPEI-INS NPs produced sustained glucose-lowering effects, promising short-term and long-term hypoglycemic efficacy in the T2DM model. Furthermore, the treatment of the CS-bPEI-INS NPs greatly protected the islet in the pancreas and prevented the associated complications of the T2DM, such as cardiac fibrosis in the myocardial interstitium and the perivascular area. In a word, the CS-bPEI-INS NPs was an encouraging long-acting formulation of insulin and had great potential in the treatment of T2DM.

Protein and peptide drugs are predominantly administered by injection to achieve high bioavailability, but this greatly compromises patient compliance. Oral and transdermal drug delivery with minimal invasiveness and high adherence represent attractive alternatives to injection administration. However, oral and transdermal administration of bioactive proteins must overcome biological barriers, namely the gastrointestinal and skin barriers, respectively. The rapid development of new materials and technologies promises to address these physiological obstacles. This review provides an overview of the latest advances in oral and transdermal protein delivery, including chemical strategies, synthetic nanoparticles, medical microdevices, and biomimetic systems for oral administration, as well as chemical enhancers, physical approaches, and microneedles in transdermal delivery. We also discuss challenges and future perspectives of the field with a focus on innovation and translation.

Ligand-modified nanocarriers (LMNCs) specific to their targets have attracted increasing interest for enhanced oral drug delivery in recent decades. Although the design of LMNCs for enhanced endocytosis and improved exposure of the loaded drugs through the oral route has received abundant attention, it remains unclear how the design influences their transcellular process, especially the key factors affecting their functions. This review discusses the extracellular and cellular barriers to orally administered LMNCs in the gastrointestinal (GI) tract and new discoveries regarding the GI protein corona and the sequential transport barriers that impede the preplanned movements of LMNCs after oral administration. Furthermore, innovative progress in considering key factors (including target selection, ligand properties, and other important factors) in the rational design of LMNCs for oral drug delivery is presented. In particular, some factors that endow LMNCs with efficient transcytosis rather than only endocytosis are highlighted. Finally, the prospects of orally administered LMNCs in disease therapy for the enhanced oral/local bioavailability of active pharmaceutical ingredients, as well as emerging delivery routes, such as lymphatic drug delivery and systemic location-specific drug release based on oral transcellular LMNCs, are discussed.

The significant growth in type 2 diabetes mellitus (T2DM) prevalence strikes a common threat to the healthcare and economic systems globally. Despite the availability of several anti-hyperglycaemic agents in the market, none can offer T2DM remission. These agents include the prominent incretin-based therapy such as glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 inhibitors that are designed primarily to promote GLP-1R activation. Recent interest in various therapeutically useful gastrointestinal hormones in T2DM and obesity has surged with the realisation that enteroendocrine L-cells modulate the different incretins secretion and glucose homeostasis, reflecting the original incretin definition. Targeting L-cells offers promising opportunities to mimic the benefits of bariatric surgery on glucose homeostasis, bodyweight management, and T2DM remission. Revising the fundamental incretin theory is an essential step for therapeutic development in this area. Therefore, the present review explores enteroendocrine L-cell hormone expression, the associated nutrient-sensing mechanisms, and other physiological characteristics. Subsequently, enteroendocrine L-cell line models and the latest L-cell targeted therapies are reviewed critically in this paper. Bariatric surgery, pharmacotherapy and new paradigm of L-cell targeted pharmaceutical formulation are discussed here, offering both clinician and scientist communities a new common interest to push the scientific boundary in T2DM therapy.

There is a growing interest in the development of lipid-based nanocarriers for multiple purposes, including the recent increase of these nanocarriers as vaccine components during the COVID-19 pandemic. The number of studies that involve the surface modification of nanocarriers to improve their performance (increase the delivery of a therapeutic to its target site with less off-site accumulation) is enormous. The present review aims to provide an overview of various methods associated with lipid nanoparticle grafting, including techniques used to separate grafted nanoparticles from unbound ligands or to characterize grafted nanoparticles. We also provide a critical perspective on the usefulness and true impact of these modifications on overcoming different biological barriers, with our prediction on what to expect in the near future in this field.

The past few years has witnessed a booming market of protein and peptide drugs, owing to their superior efficiency and biocompatibility. Parenteral route is the most commonly employed method for protein and peptide drugs administration. However, short plasma half-life protein and peptide drugs requires repetitive injections and results in poor patient compliance. Oral delivery is a promising alternative but hindered by harsh gastrointestinal environment and defensive intestinal epithelial barriers. Therefore, designing suitable oral delivery systems for peptide and protein drugs has been a persistent challenge. This review summarizes the main challenges for oral protein and peptide drugs delivery and highlights the advanced formulation strategies to improve their oral bioavailability. More importantly, major intestinal cell types and available targeting receptors are introduced along with the potential strategies to target these cell types. We also described the multifunctional biomaterials which can be used to prepare oral carrier systems as well as to modulate the mucosal immune response. Understanding the emerging delivery strategies and challenges for protein and peptide drugs will surely inspire the production of promising oral delivery systems that serves therapeutic needs in clinical settings.

Biological macromolecule-based therapeutics irrupted in the pharmaceutical scene generating a great hope due to their outstanding specificity and potency. However, given their susceptibility to degradation and limited capacity to overcome biological barriers new delivery technologies had to be developed for them to reach their targets. This review aims at analyzing the historical seminal advances that shaped the development of the protein/peptide delivery field, along with the emerging technologies on the lead of the current landscape. Particularly, focus is made on technologies with a potential for transmucosal systemic delivery of protein/peptide drugs, followed by approaches for the delivery of antigens as new vaccination strategies, and formulations of biological drugs in oncology, with special emphasis on mAbs. Finally, a discussion of the key challenges the field is facing, along with an overview of prospective advances are provided.

Dysregulated glucose metabolism is associated with many chronic diseases such as obesity and type 2 diabetes mellitus (T2DM), and strategies to restore and maintain glucose homeostasis are essential to health. The incretin hormone of glucagon-like peptide-1 (GLP-1) is known to play a critical role in regulating glucose homeostasis and dietary nutrients are the primary stimuli to the release of intestinal GLP-1. However, the GLP-1 producing enteroendocrine L-cells are mainly distributed in the distal region of the gastrointestinal tract where there are almost no nutrients to stimulate the secretion of GLP-1 under normal situations. Thus, a dietary strategy to sustain the release of GLP-1 was proposed, and the slow digestion property and dipeptidyl peptidase IV (DPP-IV) inhibitory activity of food components, approaches to reduce the rate of food digestion, and mechanisms to sustain the release of GLP-1 were reviewed. A slow digestion-oriented dietary approach through encapsulation of nutrients, incorporation of viscous dietary fibers, and enzyme inhibitors of phytochemicals in a designed whole food matrix will be implemented to efficiently reduce the digestion rate of food nutrients, potentiate their distal deposition and a sustained secretion of GLP-1, which will be beneficial to improved glucose homeostasis and health.

In this manuscript, we report the development of a versatile, robust, and stable targeting nanocarrier for active delivery. This nanocarrier is based on bifunctionalized polymeric nanoparticles conjugated to a monoclonal antibody that allows for active targeting of either (i) a fluorophore for tracking or (ii) a drug for monitoring specific cell responses. This nanodevice can efficiently discriminate between cells in coculture based on the expression levels of cell surface receptors. As a proof of concept, we have demonstrated efficient delivery using a broadly established cell surface receptor as the target, the epidermal growth factor receptor (EGFR), which is overexpressed in several types of cancers. Additionally, a second validation of this nanodevice was successfully carried out using another cell surface receptor as the target, the cluster of differentiation 147 (CD147). Our results suggest that this versatile nanocarrier can be expanded to other cell receptors and bioactive cargoes, offering remarkable discrimination efficiency between cells with different expression levels of a specific marker. This work supports the ability of nanoplatforms to boost and improve the progress towards personalized medicine.

Glucagon-like peptide-1 (GLP-1) receptor agonists are being increasingly exploited in clinical practice for management of type 2 diabetes mellitus due to their ability to lower blood glucose levels and reduce off-target effects of current therapeutics. Nanomaterials had viewed myriad breakthroughs in protecting peptides against degradation and carrying therapeutics to targeted sites for maximizing their pharmacological activity and overcoming limitations associated with their application. This review highlights the latest advances in designing smart multifunctional nanoconstructs and engineering targeted and stimuli-responsive nanoassemblies for delivery of GLP-1 receptor agonists. Furthermore, advanced nanoconstructs of sophisticated supramolecular assembly yet efficient delivery of GLP-1/GLP-1 analogs, nanodevices that mediate intrinsic GLP-1 secretion per se, and nanomaterials with capabilities to load additional moieties for synergistic antidiabetic effects, are demonstrated.

Peptides and proteins have emerged as potential therapeutic agents and, in the search for the best treatment regimen, the oral route has been extensively evaluated because of its non-invasive and safe nature. The physicochemical properties of peptides and proteins along with the hurdles in the gastrointestinal tract (GIT), such as degrading enzymes and permeation barriers, are challenges to their delivery. To address these challenges, several conventional and novel approaches, such as nanocarriers, site-specific and stimuli specific delivery, are being used. In this review, we discuss the challenges to the oral delivery of peptides and the approaches used to tackle these challenges.

Diabetes mellitus (DM) is a metabolic disorder characterized by the presence of chronic hyperglycemia driven by insulin deficiency or resistance, imposing a significant global burden affecting 463 million people worldwide in 2019. This review has comprehensively summarized the application of nanomedicine with accurate, patient-friendly, real-time properties in the field of diabetes diagnosis and monitoring, and emphatically discussed the unique potential of various nanomedicine carriers (e.g., polymeric nanoparticles, liposomes, micelles, microparticles, microneedles, etc.) in the management of diabetes and complications. Novel delivery systems have been developed with improved pharmacokinetics and pharmacodynamics, excellent drug biodistribution, biocompatibility, and therapeutic efficacy, long-term action safety, as well as the improved production methods. Furthermore, the effective nanomedicine for the treatment of several major diabetic complications with significantly improved life qualities of diabetic patients were discussed in detail. Going through the literature review, several critical issues of the nanomedicine-based strategies applications need to be addressed such as stabilities and long-term safety effects in vivo, the deficiency of standard for formulation administration, feasibility of scale-up, etc. Overall, the review provides an insight into the design, advantages and limitations of novel nanomedicine application in the diagnostics, monitoring, and therapeutics of DM.

In recent years, peptide/protein drugs have attracted considerable attention owing to their superior targeting and therapeutic effect and fewer side effects compared with chemical drugs. Oral administration modality with enhanced patient compliance is increasingly being recognized as an ideal route for peptide/protein delivery. However, the limited permeation efficiency and low oral bioavailability of peptide/protein drugs significantly hinder therapeutic advances. To address these problems, various nano and microscale delivery platforms have been developed, which offer significant advantages in oral peptide/protein delivery. In this review, we briefly introduce the transport mechanisms of oral peptide/protein delivery and the primary barriers to this delivery process. We also highlight the recent advances in various nano and microscale delivery platforms designed for oral peptide/protein delivery. We then summarize the existing strategies used in these delivery platforms to improve the oral bioavailability and permeation efficiency of peptide/protein therapeutics. Finally, we discuss the major challenges faced when nano and microscale systems are used for oral peptide/protein delivery. This review is expected to provide critical insight into the design and development of oral peptide/protein delivery systems with significant therapeutic advances.