Synergistic Effect of Toceranib and Nanohydroxyapatite as a Drug Delivery Platform-Physicochemical Properties and In Vitro Studies on Mastocytoma Cells.

A new combination of Toceranib (Toc; 5-[(5Z)-(5-Fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrrole-3-carboxamide) with nanohydroxyapatite (nHAp) was proposed as an antineoplastic drug delivery system. Its physicochemical properties were determined as crystallinity, grain size, morphology, zeta potential and hydrodynamic diameter as well as Toceranib release. The crystalline nanorods of nHAp were synthesised by the co-precipitation method, while the amorphous Toceranib was obtained by its conversion from the crystalline form during nHAp-Toc preparation. The surface interaction between both compounds was confirmed using Fourier-transform infrared spectroscopy (FT-IR), ultraviolet-visible spectroscopy (UV-Vis) and scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDS). The nHAp-Toc showed a slower and prolonged release of Toceranib. The release behaviour was affected by hydrodynamic size, surface interaction and the medium used (pH). The effectiveness of the proposed platform was tested by comparing the cytotoxicity of the drug combined with nHAp against the drug itself. The compounds were tested on NI-1 mastocytoma cells using the Alamar blue colorimetric technique. The obtained results suggest that the proposed platform shows high efficiency (the calculated IC50 is 4.29 nM), while maintaining the specificity of the drug alone. Performed analyses confirmed that nanohydroxyapatite is a prospective drug carrier and, when Toceranib-loaded, may be an idea worth developing with further research into therapeutic application in the treatment of canine mast cell tumour.

Oral nanoparticles based on gellan gum/pectin for colon-targeted delivery of resveratrol.

Nanoparticles based on gellan gum/pectin blends were designed for colon-targeted release of resveratrol (RES). Their impact on drug release rates and permeability were evaluated using Caco-2 cell model and mucus secreting triple co-culture model. Polymeric nanoparticles (PNP) were successfully prepared by nebulization/ionotropic gelation, achieving high drug loading (>80%). PNP were spherical with a low positive charge density (+5mV) and exhibited diameters of around 330 nm. Developed PNP were able to promote effective modulation of drug release rates, so that only 3% of RES was released in acidic media over 2 h, and, in pH 6.8, the drug was released in a sustained manner, reaching 85% in 30 h. The permeability of RES-loaded PNP in the Caco-2 model was 0.15%, while in the triple co-culture model, in the presence of mucus, it reached 5.5%. The everted gut sac experiment corroborated the low permeability of RES-loaded PNP in the presence or absence of mucus and highlighted their high ability to interact with the intestinal tissue. Results indicate that the novel PNP developed in this work are safe and promising carriers for controlled delivery of RES at the colon.

Applications and Limitations of Dendrimers in Biomedicine.

Biomedicine represents one of the main study areas for dendrimers, which have proven to be valuable both in diagnostics and therapy, due to their capacity for improving solubility, absorption, bioavailability and targeted distribution. Molecular cytotoxicity constitutes a limiting characteristic, especially for cationic and higher-generation dendrimers. Antineoplastic research of dendrimers has been widely developed, and several types of poly(amidoamine) and poly(propylene imine) dendrimer complexes with doxorubicin, paclitaxel, imatinib, sunitinib, cisplatin, melphalan and methotrexate have shown an improvement in comparison with the drug molecule alone. The anti-inflammatory therapy focused on dendrimer complexes of ibuprofen, indomethacin, piroxicam, ketoprofen and diflunisal. In the context of the development of antibiotic-resistant bacterial strains, dendrimer complexes of fluoroquinolones, macrolides, beta-lactamines and aminoglycosides have shown promising effects. Regarding antiviral therapy, studies have been performed to develop dendrimer conjugates with tenofovir, maraviroc, zidovudine, oseltamivir and acyclovir, among others. Furthermore, cardiovascular therapy has strongly addressed dendrimers. Employed in imaging diagnostics, dendrimers reduce the dosage required to obtain images, thus improving the efficiency of radioisotopes. Dendrimers are macromolecular structures with multiple advantages that can suffer modifications depending on the chemical nature of the drug that has to be transported. The results obtained so far encourage the pursuit of new studies.

Tetrazine Carbon Nanotubes for Pretargeted In†Vivo "Click-to-Release" Bioorthogonal Tumour Imaging.

The bioorthogonal inverse-electron-demand Diels-Alder (IEDDA) cleavage reaction between tetrazine and trans-cyclooctene (TCO) is a powerful way to control the release of bioactive agents and imaging probes. In this study, a pretargeted activation strategy using single-walled carbon nanotubes (SWCNTs) that bear tetrazines (TZ@SWCNTs) and a TCO-caged molecule was used to deliver active effector molecules. To optimize a turn-on signal by using in vivo fluorescence imaging, we developed a new fluorogenic near-infrared probe that can be activated by bioorthogonal chemistry and image tumours in mice by caging hemicyanine with TCO (tHCA). With our pretargeting strategy, we have shown selective doxorubicin prodrug activation and instantaneous fluorescence imaging in living cells. By combining a tHCA probe and a pretargeted bioorthogonal approach, real-time, non-invasive tumour visualization with a high target-to-background ratio was achieved in a xenograft mice tumour model. The combined advantages of enhanced stability, kinetics and biocompatibility, and the superior pharmacokinetics of tetrazine-functionalised SWCNTs could allow application of targeted bioorthogonal decaging approaches with minimal off-site activation of fluorophore/drug.

Double Drug Delivery Using Capped Mesoporous Silica Microparticles for the Effective Treatment of Inflammatory Bowel Disease.

Silica mesoporous microparticles loaded with both rhodamine B fluorophore (S1) or hydrocortisone (S2), and capped with an olsalazine derivative, are prepared and fully characterized. Suspensions of S1 and S2 in water at an acidic and a neutral pH show negligible dye/drug release, yet a notable delivery took place when the reducing agent sodium dithionite is added because of hydrolysis of an azo bond in the capping ensemble. Additionally, olsalazine fragmentation induced 5-aminosalicylic acid (5-ASA) release. In vitro digestion models show that S1 and S2 solids are suitable systems to specifically release a pharmaceutical agent in the colon. In vivo pharmacokinetic studies in rats show a preferential rhodamine B release from S1 in the colon. Moreover, a model of ulcerative colitis is induced in rats by oral administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) solutions, which was also used to prove the efficacy of S2 for colitis treatment. The specific delivery of hydrocortisone and 5-ASA from S2 material to the colon tissue in injured rats markedly lowers the colon/body weight ratio and the clinical activity score. Histological studies showed a remarkable reduction in inflammation, as well as an intensive regeneration of the affected tissues.

Improvement in bioactive protein storage stability and colon-targeted release: a simple double-layer chitosan-based particle.

Aim: To improve the long-term storage stability of a bioactive protein and the subsequent colon-targeted release, a double-layer chitosan (CS)-based particle was developed. Methods: To form the double-layer CS-based particle, the second layer was crosslinked onto the single-layer bovine serum albumin (BSA)-loaded CS-based particle. The structure and properties of particles were further investigated. Results: With the second layer, the double-layer particles became more compact, which was important for the inhibition of bioactive protein leakage during storage through strong electrostatic interactions and swelling of the hydrogels. After 30 d of storage, there was only 43.74-49.32% BSA leakage from the C15-TPP/C15-HMP double-layer particles. Moreover, the BSA release in subsequent colon-targeted delivery after storage was 44.02-48.59%. Conclusions: With double-layer shielding and a more compact arrangement, it was possible to reduce bioactive protein leakage over long periods storage and achieve subsequent colon-targeted delivery.

pH-Triggered Hydrogel Nanoparticles for Efficient Anticancer Drug Delivery and Bioimaging Applications.

In this work, we developed multifunctional hydrogel nanoparticles (NPs) that can encapsulate anticancer drugs and imaging contrast agents as well. Mitomycin C (MMC) and rhodamine B (RB) were selected as models for anticancer drugs and imaging contrasting agents, respectively. Both MMC and RB were linked to the succinated polyvinyl alcohol polymer (PVA-SA). The selected labeled hydrogel NPs ((0.5% RB)-PVA-SA NPs and (1.5% RB)-PVA-SA NPs) improved the RB quantum yield from 29.8% to a minimum of 42.7%. Moreover, they showed higher emission stability compared to free RB when they were repeatedly excited at 554 nm for 2 h. Furthermore, the dye polymeric interactions significantly increased the RB fluorescence lifetime by approximately twofold. All these optical properties pave the way for our labeled hydrogel NPs to be used in imaging-guided therapy. For the labeled MMC-loaded NPs, the MMC-binding efficiency was found to be exceedingly high in all synthesized samples: a minimum of 92% was achieved. In addition, the obtained pH-dependent drug release profiles as well as the cytotoxicity evaluation demonstrated the high potential of releasing MMC under acidic cancerous conditions. Moreover, the in vitro cellular uptake experiment confirmed the accumulation of MMC NPs throughout the cytoplasm.

Shellac-based delivery systems for food bioactive compounds.

Shellac is a natural resin featuring some attractive properties such as amphiphilicity, pH responsiveness, biocompatibility, and biodegradability. There has been increasing interest in employing shellac for controlled delivery of food bioactive compounds. This review outlines the recent advances in different types of shellac-based delivery systems, including nanoparticles, zein-shellac particles, hydrogels, nanofibers, and nanomicelles. The preparation method, formation mechanism, structure, and delivery performance are investigated. These systems could improve the stability and shelf-life of bioactive compounds, allow for targeted release at the small intestine or colon site, and increase bioavailability. The deficiencies and challenges of each of the systems are also discussed. The promising results in this review could guide future trends in more efficient shellac-based delivery platforms for functional food applications.

Cyclodextrin-based metal-organic frameworks transforming drug delivery.

Cyclodextrin-based metal-organic frameworks (CD-MOFs) are gaining traction in the realm of drug delivery due to their inherent versatility and potential to amplify drug efficacy, specificity, and safety. This article explores the predominant preparation techniques for CD-MOFs, encompassing methods like vapor diffusion, microwave-assisted, and ultrasound hydrothermal approaches. Native CD-MOFs present compelling advantages in drug delivery applications. They can enhance drug loading capacity, stability, solubility, and bioavailability by engaging in diverse interactions with drugs, including host-guest, hydrogen bonding, and electrostatic interactions. Beyond their inherent properties, CD-MOFs can be customized as drug carriers through two primary strategies: co-crystallization with functional components and surface post-modifications. These tailored modifications pave the way for controlled release manners. They allow for slow and sustained drug release, as well as responsive releases triggered by various factors such as pH levels, glutathione concentrations, or specific cations. Furthermore, CD-MOFs facilitate targeted delivery strategies, like pulmonary or laryngeal delivery, enhancing drug delivery precision. Overall, the adaptability and modifiability of CD-MOFs underscore their potential as a versatile platform for drug delivery, presenting tailored solutions that cater to diverse biomedical and industrial needs.

Diagnosing and Treating IgAN: Steroids, Budesonide, or Maybe Both?

IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, is characterized by a mesangial IgA deposit and a variety of histological lesions, as described by the Oxford classification system. Despite the well-described "four-hit hypothesis", there are still plenty of less or undescribed mechanisms that participate in the disease pathogenesis, such as B-cell priming, which seems to be initiated by different antigens in the intestinal microbiota. Diagnosis of the disease is currently based on kidney biopsy findings, as the sensitivity and specificity of the many serum and urinary biomarkers described so far do not seem to have diagnostic accuracy. Therapeutic strategies consist of the initial step of non-immune medication, aiming to reduce both the intraglomerular pressure and proteinuria to below 0.5 g/day, followed by systemic corticosteroid administration in patients who remain at high risk for progressive chronic kidney disease despite the maximum non-immune treatment. The 6-month systemic corticosteroid treatment reduces proteinuria levels; however, the increased possibility of adverse events and increased relapse rate after treatment raises the need for a new therapeutic approach. Targeted-release budesonide is a therapeutic modality that aims to inhibit disease pathogenetic pathways at early stages; it has minor systemic absorption and proven beneficial effects on renal function and proteinuria. In the present systemic review, the benefits and adverse events of steroids and budesonide are described, and the possibility of combined treatment is questioned in selected cases with active histologic lesions.

A controlled-release nanocarrier with extracellular pH†value driven tumor targeting and translocation for drug delivery.

This pHLIP is no flop: Functionalizing mesoporous silica nanoparticles (MSNs) with pHLIPss peptide provides a controlled-release nanoparticle drug delivery system targeting the acidic tumor microenvironment. At low pH values, pHLIPss inserts into the cell membrane and translocates carriers into cells, where the cargo is released by the cleavage of the pHLIPss disulfide bonds (see scheme).

Construction and efficacy evaluation of chitosan-based nanoparticles for colon-targeted release of linoleic acid in rat pups.

Long chain fatty acids in the colon play important roles in infant development. This study aimed to establish a colon-targeted long chain fatty acid release system in rat pups, with linoleic acid (LA) as the target model. LA-loaded chitosan nanoparticles (LA-CS NPs) synthesized via ionic crosslinkage showed spherical surface morphology and favorable encapsulation efficiency (84.96 %). In vivo distribution studies of LA-CS NPs demonstrated a significant increase in LA concentration in the colonic content after a 12-hour administration period. Additionally, oral administration of the delivery system (CS NPs: 18 µg/g/d, LA-CS NPs: 24 µg/g/d) exhibited no detrimental effects on the health of rat pups. In conclusion, this study presents a promising strategy for the targeted delivery of fatty acid to the colon in rat pups.

Intestine-targeted high internal phase Pickering emulsion formulated using silkworm pupa protein via ultrasonic treatment.

High internal phase Pickering emulsions (HIPPEs) stabilized by food grade particles have received much attention as deliver vehicles for bioactives in recent years. In this study, ultrasonic treatment was conducted to regulate the size of silkworm pupa protein (SPP) particles, fabricating oil-in-water (O/W) HIPPEs with intestinal releasability. Briefly, the pretreated SPP and SPP-stabilized HIPPEs were characterized, and the targeting release was investigated using in vitro gastrointestinal simulations and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Results revealed ultrasonic treatment time was the key factor regulating emulsification performance and stability of HIPPEs. Optimized SPP particles were obtained based on their size and zeta potential of 152.67 nm and 26.77 mV, respectively. With ultrasonic treatment, the hydrophobic groups in the secondary structure of SPP were exposed, facilitating the formation of a stable oil-water interface for HIPPEs. Additionally, SPP-stabilized HIPPE showed high stable against the gastric digestion. The SPP with 70 kDa molecular weight, which was the major interfacial proteins of the HIPPE, can be hydrolyzed by intestinal digestive enzymes, enabling the intestine-targeted release of the emulsion. Overall, in the present study, a facile method was developed to stabilize HIPPEs using solo SPP with ultrasonic treatment to protect and deliver hydrophobic bioactive ingredients.

Systemic and targeted steroids for the treatment of IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is a common glomerulonephritis partially correlated with mucosal immune system dysfunction. Progressive renal failure occurs in many patients, with about 30-50% of the patients with IgAN developing end-stage kidney disease (ESKD). Many treatments have been used for decades, despite uncertainty about their effectiveness and the ideal dose. Randomised controlled trials reported that systemic glucocorticoids can be an effective treatment for patients with persistent and significant proteinuria despite renin-angiotensin system inhibitors use possibly causing systemic side effects. The primary focus of IgAN management should be based on optimised supportive care, including renin-angiotensin system (RAS) blockade and now SGLT2 inhibitors. The novel targeted-release formulation (TRF) of budesonide has been tested to reduce the adverse events of systemic steroids by delivering the drug to the distal ileum. The local efficacy of TRF-budesonide may represent a novel and promising approach to treating IgAN. Two clinical trials showed that TRF-budesonide could significantly reduce proteinuria and haematuria and possibly preserve renal function while significantly reducing the side effects. However, the limited number of treated patients and the relatively short follow-up suggest caution before considering budesonide superior to the current six-months steroid pulses scheme. Long-term data on the efficacy and safety of TRF budesonide are awaited, together with the design of trials with a head-to-head comparison with systemic steroids before considering TRF-budesonide as the standard of care treatment for IgAN nephropathy.

Gastrointestinal pH-Sensitive Pickering Emulsions Stabilized by Zein Nanoparticles Coated with Bioactive Glycyrrhizic Acid for Improving Oral Bioaccessibility of Curcumin.

Pickering emulsions have received considerable attention for their stability and functionality. Environmentally responsive Pickering emulsions could be used as vehicles for oral administration. However, challenges still exist, such as nonbiocompatibility of emulsifier and mismatched response behavior in the gastrointestinal environment. In this study, a strategy was proposed that bioactive saponin glycyrrhizic acid (GA) was used as a pH-responsive substance to functionalize zein nanoparticles, and tannic acid (TA) was used as a primer for cross-linking GA and zein nanoparticles. The Pickering emulsions fabricated by zein/TA/GA nanoparticles (ZTGs) exhibited excellent stability at acid conditions while slowly demulsifying at neutral conditions, which can be further used as an intestine-targeted delivery system. Curcumin was encapsulated into ZTG-stabilized Pickering emulsions, and the encapsulation efficiency results suggested that the presence of GA coating remarkably facilitated the encapsulation of curcumin. An in vitro digestion study suggested that ZTGs provided protection for emulsions from pepsin hydrolysis and exhibited higher free fatty acid release as well as higher bioaccessibility of curcumin during simulated intestine digestion. This study provides an effective strategy to prepare pH-responsive Pickering emulsions for improving the oral bioaccessibility of hydrophobic nutraceuticals.

Cost-Effectiveness Analysis of Nefecon versus Best Supportive Care for People with Immunoglobulin A Nephropathy (IgAN) in the United States.

Purpose: To estimate the cost-effectiveness of Nefecon in addition to the best supportive care (BSC) vs BSC in a hypothetical cohort of commercially insured adult patients with primary immunoglobulin A nephropathy (IgAN) from a United States (US) societal perspective. Methods: A lifetime horizon, semi-Markov model was developed that consisted of nine health states: chronic kidney disease (CKD) stage 1, 2, 3a, 3b, 4, end-stage renal disease (ESRD) with dialysis, ESRD without dialysis, post-kidney transplant, and death. Health state occupancy was estimated from individual patient-level data from the Phase 3 randomized controlled trial NefIgArd Part A (NCT03643965). Additional scenarios evaluated the impact of varying the time horizon, discounting, costs included, rounds of treatment, and the method used to calculate transition probabilities. Results: In the deterministic base case analysis over a lifetime horizon, Nefecon plus BSC (hereafter Nefecon) had an incremental cost of $3,810 vs BSC. Nefecon resulted in a mean survival gain of 0.247 quality-adjusted life years (QALYs), 0.195 life years (LYs), and 0.244 equal value life years (evLYs) vs BSC alone - this resulted in incremental cost-effectiveness ratios (ICERs) of $15,428 per QALY, $19,502 per LY, and $15,611 per evLY gained. Probabilistic sensitivity analyses estimated that with willingness to pay thresholds of $100,000, $150,000, and $250,000 per QALY gained, Nefecon would be cost-effective over BSC in 66.70%, 75.02%, and 86.82% of cases, respectively. In the scenario analysis, Nefecon remained cost-effective with 4 rounds of treatment. Conclusion: Nefecon was associated with LY and QALY gains vs BSC, with an incremental cost of $3,810. Based on these values, with a willingness to pay threshold of $100,000 per QALY gained, Nefecon was found to be a cost-effective treatment for US adults with primary IgAN.

Ultrasound-assisted multilayer Pickering emulsion fabricated by WPI-EGCG covalent conjugates for encapsulating probiotics in colon-targeted release.

This study demonstrated the influences of ultrasound-assisted multilayer Pickering double emulsion capsules on the pasteurization and gastrointestinal digestive viability of probiotic (L. plantarum) strain liquid. Firstly, the role of ultrasonic homogenization on the morphology of W1/O/W2 double emulsions were studied. The double emulsion formed by ultrasonic intensity at 285 W had a single and narrow distribution with smallest droplet size. The double emulsion particles were then coated with chitosan(Chi), alginate (Alg), and CaCl2(Ca). The multilayer emulsion after pasteurization and gastrointestinal digestion both had the highest viability at 5 coating layers, but its particle size (108.65 µm) exceeded the limit of human oral sensory (80 µm). It could be noted that the deposition of 3-4 layers of coating had similar activity after pasteurization/GIT digestion. And droplets with 3 layers of coating were the minimum and most available formulation for encapsulated probiotics (L. plantarum). Hence, the results suggest that the use of ultrasound-assisted multilayer emulsions encapsulated with probiotics in granular food and pharmaceutical applications is a promising strategy.

Current knowledge of targeted-release budesonide in immunoglobulin A nephropathy: A comprehensive review.

Immunoglobulin A (IgA) nephropathy is a common autoimmune kidney disease. Accumulating studies showed that IgA nephropathy may be partially correlated with mucosal immune system dysfunction. Systemic corticosteroid treatment exerts an essential protective effect against renal deterioration in IgA nephropathy. However, long-term use of corticosteroids may cause systemic side effects. The novel targeted-release formulation (TRF) of budesonide has been shown to deliver the drug to the distal ileum with the aim of minimizing adverse events for patients with IgA nephropathy. In this review, we have summarized all the current evidence of the effects of TRF-budesonide protecting against IgA nephropathy. Three randomized controlled trials (RCTs), one cohort, two case reports, and an ongoing Phase 3 trial (Part B, NCT03643965), were under comprehensive review. These included studies demonstrated that TRF-budesonide could remarkably reduce proteinuria, hematuria, and creatinine, as well as preserve renal function. The local immunosuppressive effects exhibited by TRF-budesonide may represent a novel and promising approach to treating IgA nephropathy. However, the current evidence was only derived from limited trials. Therefore, more well-designed RCTs are still warranted to validate the curable profile of TRF-budesonide in treating IgA nephropathy.

Chemoprevention by Microencapsulated Lactiplantibacillus Plantarum LAB12 Against Orthotopic Colorectal Cancer Mice is Associated with Apoptosis and Anti-angiogenesis.

The pathogenesis of colorectal cancer (CRC) is associated with gut dysbiosis that is attributed to unhealthy lifestyles and dietary habits. Consumption of microencapsulated probiotics may potentially restore the gut microbiota in favour of prevention against CRC. This study determined the fate of microencapsulated Lactiplantibacillus plantarum (formerly known as Lactobacillus plantarum) LAB12 in the gastrointestinal tract (GIT) and assessed the chemopreventive effect of microencapsulated L. plantarum LAB12 in vivo. The targeted release of L. plantarum LAB12 from Alg-based microcapsules at the stomach, ileum, caecum and colon of Sprague-Dawley rats was examined by confocal microscopy and qPCR. Microcapsules loaded with L. plantarum LAB12 remained intact in the stomach. Free L. plantarum LAB12 were present in abundance (> 7 log CFU) only in the intestines. Subsequently, the chemopreventive properties of microencapsulated L. plantarum LAB12 were validated against NU/NU nude mice bearing orthotopic transplanted CT-26 CRC (12 female mice; 4-6 weeks old; 20-22 g; n = 6/group). Orthotopic mice pre-supplemented with microencapsulated L. plantarum LAB12 (10 log CFU kg-1 BW for 11 weeks) were presented with significantly (p < 0.05) reduced tumour volume (- 98.87%) and weight (- 89.27%) when compared to control. Western blots indicated that the chemopreventive effect could be attributed to apoptosis and anti-angiogenesis mediated, at least in part, through upregulation of tumour suppressor p53 (+ 45.4%) and pro-apoptotic caspase-3 (+ 82.4%), and downregulation of pro-inflammatory COX-2 (- 57.9%), pro-angiogenic VEGF (- 66.8%) and PECAM-1 (-64.1%). Altogether, this study strongly implied the possibility of having L. plantarum LAB12-loaded microcapsules safely incorporated into food and nutraceutical products for prevention against CRC.

Recent advances in oral delivery of bioactive molecules: Focus on prebiotic carbohydrates as vehicle matrices.

Controlled oral delivery of bioactive molecules remains a promising platform for the food and biomedical realm. Nonetheless, there are many bottlenecks to the efficient oral bioactive delivery that necessitates the development of advanced approaches. In recent years, prebiotic carbohydrates have drawn surging interest for targeted bioactive delivery due to their potential of multi-stimuli release mechanisms. Harnessing prebiotic-based vehicles confers novel possibilities for intact oral bioactive delivery, improving their bioavailability and efficacy. This critical review updates state of the art on progresses in oral delivery of natural active agents via prebiotic carbohydrates. We offer the latest advances concerning prebiotic-based vehicles (i.e., pH/time-dependent systems, enzyme-sensitive polymers, and colonic microbiota-dependent vehicles), emphasizing their key attributes to attaining controlled/targeted bioactive delivery to the intended locus. Finally, we discuss safety considerations, challenges, and future perspectives toward advances in the field.