Oral administration has long been considered the most convenient method of drug delivery, requiring minimal expertise and invasiveness. Unlike injections, it avoids discomfort, wound infections, and complications, leading to higher patient compliance. However, the effectiveness of oral delivery is often hindered by the harsh biological barriers of the gastrointestinal tract, which limit the bioaccessibility and bioavailability of drugs. The development of oral drug delivery systems (ODDSs) represents a critical area for the advancement of pharmacotherapy. This review highlights the characteristics and precise targeting mechanisms of ODDSs. It first examines the unique properties of each gastrointestinal compartment, including the stomach, small intestine, intestinal mucus, intestinal epithelial barrier, and colon. Based on these features, it outlines the targeting strategies and design principles for ODDSs aimed at overcoming gastrointestinal barriers to enhance disease treatment. Lastly, the review discusses the challenges and potential future directions for ODDS development, emphasizing their importance for advancing drug delivery technologies and accelerating their future growth.

Oral administration is a traditional, safe, and widely used drug delivery strategy. However, the delivery efficiency of the oral drug delivery system is hindered by the long gastrointestinal tract, filled with dense and viscous mucus. Herein, we presented an acoustic-magnetic responsive nanomotor (MMSNP) for oral drug delivery via gastrointestinal site navigation and mucus layer penetration. MMSNP has a Janus rod-shaped structure composed of iron tetroxide and mesoporous silica, which could be guided to various intestinal segments with an external magnetic field based on the demand of different diseases. In addition, the rod-like system could effectively penetrate the dense and viscous mucus under ultrasound radiation to improve the bioavailability of loaded drugs. In diabetes rats, small intestinal navigation and mucus penetration of the nanomotor increased the oral relative bioavailability of metformin (Met) by 78.0% and the effective hypoglycemic time by 1.1-fold than pure Met. In orthotopic colorectal cancer (CRC)-bearing mice, magnetically mediated colorectal navigation increased the anchoring efficiency of nanomotors by 4.2-fold, and ultrasound propulsion increased the mucus penetration efficiency of MMSNP by 5.2-fold, leading to a vastly improved delivery efficiency of cisplatin (CP) and a superior tumor inhibition rate of 97.2%. This simple and versatile nanomotor has broad application prospects in the treatment of gastrointestinal diseases, providing a promising and universal strategy for clinical conversion of orally administered drugs.

The oral administration of drugs for cancer therapy can maintain optimal blood concentrations, is biologically safe and simple, and is preferred by many patients. However, the complex lumen environment, mucus layer, and intestinal epithelial cells are biological barriers that hinder the absorption of orally administered drugs. In this study, sea urchin-like manganese-doped copper selenide nanoparticles (Mn-Cu2-xSe NPs) were designed using an anion exchange method and coated with calcium alginate and chitosan (AC) to form Mn-Cu2-xSe@AC capsules. The pH-responsive swelling behavior of the AC protective layer aided doxorubicin (DOX)-loaded Mn-Cu2-xSe NPs in overcoming multiple biological barriers, maintained their stability in gastric acid, and facilitated the release of the NPs in the small intestine. The intestinal epithelial cell permeability of DOX/Mn-Cu2-xSe NPs was confirmed using a monolayer absorption model involving Caco-2 human epithelial cells. The released DOX/Mn-Cu2-xSe NPs smoothly passed through the mucus layer, and were absorbed by intestinal epithelial cells. In mice, the NPs circulated in the blood and passively targeted the tumors through blood circulation by enhancing the permeability and retention effect to achieve significant tumor suppression and reduce damage to normal tissues. In addition, the unique sea urchin-like morphology of Mn-Cu2-xSe NPs enhanced the absorption in the near-infrared-II (NIR-II) window for photothermal therapy, realized the near-infrared-stimulated response release of DOX for increased chemotherapy, and promoted the Fenton-like effect because of the doping of manganese ions for chemodynamic therapy. These effects could permit the development of various synergistic cancer treatments. The use of DOX/Mn-Cu2-xSe@AC capsules as a multistage oral drug delivery system may overcome the sequential absorption barriers that currently hinder chemotherapy, chemodynamic, and photothermal therapies.

Oral drug delivery plays a key role in the treatment of colon cancer. In this study, as a novel oral delivery system, drug tanshinone IIA (Tan IIA) was firstly loaded into β-cyclodextrin (β-CD) to prepare Tan IIA@β-CD, which was subsequently encapsulated by Eucommia ulmoides rubber (EUR)/acetylated starch (AS) film to endow it colon-targeted drug release function. The constructed EUR/AS/Tan IIA@β-CD was characterized using zeta potential, FT-IR, UV-vis, XRD, TG, SEM, and TEM. Moreover, in vitro release experiments revealed that the composite at optimal AS content (95 %) showed Tan IIA cumulative release rate of only 10 % in SGF, while it can reach the maximum value of 23 % in SIF. Analysis of drug release mechanism revealed two mainly distinct processes: erosion in SGF and diffusion in SIF. Furthermore, in vivo anticancer effect was evaluated in mice with orthotopic colon cancer model. After 28 days, compared to Tan IIA@β-CD group, the tumor volume and weight in EUR/AS/Tan IIA@β-CD group were decreased by 20.0 % and 34.6 %, respectively. Histological analyses showed that EUR/AS film significantly enhanced the available treatment against colon cancer cells. The proposed EUR/AS/Tan IIA@β-CD system shows great potential for colon-targeted drug delivery and enhancing the therapeutic efficacy of colon cancer.

Colon cancer has a complex microenvironment and course, and conventional chemotherapy is hindered by low permeability and immunosuppression at the cancer site, leading to poor efficacy. Integrating intestinal environment regulation and molecularly targeted drugs are more attractive strategies. This study aimed to developed an oral colonic targeted delivery system (5-Flu/MET@MSNs/Ce6@HIL) using hyaluronic acid (HA) and inulin (IN) as key components. IN is a polymer with colon-specific targeting capabilities, while HA targets CD44 on the surface of colon cancer cells. We used IN and HA-modified liposomes to co-encapsulate three therapeutic agents, chemotherapy drug 5-Fluorouracil (5-Flu), photosensitizer chlorin e6 (Ce6), and hypoxia reliever metformin (MET). 5-Flu and Ce6 effectively induced cell apoptosis, whereas MET downregulated Hypoxia-Inducible Factor 1-α (HIF-1α) and alleviate the hypoxic microenvironment. In orthotopic colon-tumor-bearing-mice, the final product of 5-Flu@MET@MSNs/Ce6@HIL effectively hindered growth of tumors, which was inhibited by 3.31, 14.31, and 7.88 times when compared to 5-Flu, MET, or Ce6 single-loaded formulations, respectively. Furthermore, after oral administration, the multifunctional liposomes showed good in vivo safety and compliance. In conclusion, this study proposes a novel orthotopic colon-targeted cancer treatment strategy with accurate tumor targeting capabilities, which has certain potential and development value in future clinical applications.

Activation of the epithelial-mesenchymal transition (EMT), a pivotal process in tumor metastasis and evasion, as well as the NLRP3 inflammasome, both promote colorectal cancer (CRC) progression. Recent studies have shown that Transmembrane protein 176B (TMEM176B) regulates NLRP3 and promotes CRC malignant phenotypes.

To investigate the role of TMEM176B in modulating NLRP3 inflammasome and its implications on EMT and tumor progression in CRC.

CRC in situ mouse and co-cultured cell models were established using CT26 cells, BALB/c mice, and primary cultured mouse natural killer (NK) cells. Short hairpin RNA knocked down TMEM176B and NLRP3 expression in CT26 cells. Fluorescence imaging, Terminal deoxynucleotidyl transferase dUTP nick end labeling assays, immunohistochemistry staining, flow cytometry, and molecular assays were used to investigate the effects of TMEM176B knockdown on the NLRP3 inflammasome in NK cells to assess tumor metastasis, apoptosis, and EMT indicators.

Silencing TMEM176B in CRC mice significantly reduced tumor metastasis, proliferation, and EMT, while activating apoptosis, NLRP3 inflammasome, and NK cell activity. Furthermore, silencing TMEM176B in co-cultured cell models inhibited cell migration and invasion, and promoted apoptosis. The interference of NLRP3 reversed these effects by modulating key proteins such as phosphorylated nuclear factor kappa B subunit 1 p65, matrix metallopeptidase 9, and transforming growth factor-β.

This study highlights the critical role of TMEM176B/NLRP3 in CRC progression and provides a basis for targeting this axis as a novel therapeutic approach to manage CRC progression and metastasis.

In order to decipher the relationship between gut microbiota imbalance and cancer, this paper reviewed the role of intestinal microbiota in anticancer therapy and related mechanisms, discussed the current research status of gut microbiota as a biomarker of cancer, and finally summarized the reasonable means of regulating gut microbiota to assist cancer therapy. Overall, our study reveals that the gut microbiota can serve as a potential target for improving cancer management.

Due to the poor solubility, permeability, stability and tumor-targeting ability of norcantharidin (NCTD), currently commercially available NCTD formulations require patients to take the medicine more frequently. Moreover, the formulation of NCTD themselves have certain toxicity, thus showing unsatisfactory therapeutic outcomes and serious systemic side effects. Based on the specific acidic environment at the tumor site, in this study, the pH-sensitive NCTD solid self-microemulsion (NCTD@CS-DMMA SSME) was prepared by introducing 2,3-dimethylmaleic acid amide modified chitosan (CS-DMMA), and it was wrapped in colon-coated capsule to achieve stable and controlled drug release in the acidic environment of colonic tumors. After self-emulsification, it had a particle size of 75.88 ± 0.85 nm and carried a negative charge. Under the condition of pH 6.5, NCTD@CS-DMMA SSME exhibited first-order release kinetics characteristics. Moreover, the cumulative release under the condition of pH 6.5 was 2.04-fold higher than that under the condition of pH 7.4. The in situ intestinal absorption assay elucidated that the prepared formulation could effectively improve the absorption rate constant and apparent permeability coefficients of NCTD in colon tumor site. The antitumor effect in vivo and in vitro showed that it could not only improve the inhibition ability of tumor growth, migration and invasion in mice, but also increase the tumor-infiltrating T lymphocytes in mice with colon cancer, thus inhibiting tumor growth. In summary, the NCTD@CS-DMMA SSME can deliver drugs to the site of colon tumors and continuously release drugs, providing new insights into improving the treatment effectiveness of colon cancer.

Inflammatory bowel disease (IBD) is a chronic inflammatory bowel disease with no clinical cure. Excessive production of reactive oxygen species (ROS) at the inflammatory sites leads to the onset and progression of IBD. And the current non-invasive imaging methods are not ideal for the diagnosis and monitoring of IBD.

Herein, we developed inulin (IN)-coated cerium oxide nanoparticles (CeO2@IN NPs) for treatment and monitoring of IBD guided by computed tomography (CT). The physicochemical properties, ROS scavenging ability and CT imaging capabilities of CeO2@IN were investigated in vitro. Moreover, the therapeutic and targeted inflammation imaging effects of CeO2@IN were validated in dextran sulfate sodium (DSS)-induced colitis model.

CeO2@IN with catalase (CAT) and superoxide dismutase (SOD) capabilities effectively scavenged ROS, thus protecting the cells against oxidative stress. In colitis model mice, orally administered CeO2@IN successfully traversed the gastrointestinal tract to reach the colon under the protection of IN, and effectively reduced intestinal inflammation, thereby maintaining the intestinal epithelial integrity. Notably, CeO2@IN performed better than conventional CT contrast agents for gastrointestinal tract imaging, particularly in detecting the inflamed areas in the colon. In addition, CeO2@IN exhibited excellent biocompatibility in vitro and in vivo.

The study provided a novel integrated diagnostic and therapeutic tool for the treatment and monitoring of IBD, presenting great potential as a clinical application for IBD.

The therapeutic outcomes of medications were restricted by the colonic mucosal barrier during the treatment of colorectal cancer (CRC). Micro/nanomotors can overcome the mucus barriers to reach deep colorectal tumors. In this study, we constructed a novel microsized PLGA-Pt micromotor (MM) driven by hydrogen peroxide (H2O2) to enhance drug delivery to the CRC tissues and achieve effective antitumor therapy. The PLGA-Pt MMs actively traversed the colonic mucosal barrier with the assist of gas propulsion, while continuously releasing Pt2+ ions within the tumor microenvironment. In vitro studies revealed that the PLGA-Pt MMs exhibited rapid movement in the presence of H2O2, achieving superior colonic mucosal penetration. It effectively delivered Pt2+ ions to the nuclei, forming DNA-Pt adducts that induced significant DNA damage and apoptosis of CRC cells. In vivo studies showed the PLGA-Pt MM significantly suppressed orthotopic tumor growth and activated antitumor immunity, enhancing the therapeutic effect against CRC. This study presents a micromotor capable of overcoming mucosal barriers for efficient treatment of orthotopic CRC.

In this study, phthalate inulin nanoparticles (PINs) were chemically modified and characterized. The internalization of PINs into the probiotic E. faecalis, which delivering Fiber2 protein of fowl adenovirus serotype 4 (FAdV-4), was investigated. The expression of the Fiber2 protein in E. faecalis was detected using western blot analysis. To protect recombinant E. faecalis from degradation of in the gastric acid environment, sodium alginate was used to encapsulate the bacteria. The survival ratio and release of E. faecalis in simulated gastrointestinal fluid was assessed. Oral administration of microencapsulated E. faecalis loaded with PINs (Micro-E/Fiber2-PINs) or inulin (Micro-E/Fiber2-inulin) was conducted, followed by an experimental challenge with FAdV-4 in chickens to evaluate immune responses and protection. The results showed the internalization of PINs into the bacteria promoted bacteria growth, and significantly improved the expression level of Fiber2. After incubation in simulated gastric fluid, the number of viable bacteria from the Micro-E/Fiber2-PINs group was significantly higher than that from the E. faecalis/Fiber2 group. The release of bacteria from the microcapsules was completed within 30 min. Animal experiments demonstrated that oral immunization with Micro-E/Fiber2-PINs significantly enhanced humoral and cellular immune responses, relieved inflammatory injury in FAdV-targeted organs, and improved survival rate of challenged chickens. This study presents promising potential for developing oral vaccines against pathogen infection.

Chemotherapy is widely recognized as a highly efficacious modality for cancer treatment, involving the administration of chemotherapeutic agents to target and eradicate tumor cells. Currently, oral administration stands as the prevailing and widely utilized method of delivering chemotherapy drugs. However, the majority of anti-tumor medications exhibit limited solubility and permeability, and poor stability in harsh gastrointestinal environments, thereby impeding their therapeutic efficacy for chemotherapy. Therefore, more and more micro-nano drug delivery carriers have been developed and used to effectively deliver anti-cancer drugs, which can overcome physiological barriers, facilitate oral administration, and ultimately improve drug efficacy. In this paper, we first discuss the effects of various biological barriers on micro-nano drug carriers and oral administration approach. Then, the development of micro-nano drug carriers based on various biomedical components, such as micelles, dendrimers, hydrogels, liposomes, inorganic nanoparticles, etc. were introduced. Finally, the current dilemma and the potential of oral drug delivery for clinical treatment were discussed. The primary objective of this review is to introduce various oral delivery methods and serve as a point of reference for the advancement of novel oral delivery carriers, with the ultimate goal of informing the development of future clinical applications.

S-Adenosylmethionine (SAMe) is a crucial endogenous molecule in vital biochemical processes such as DNA, RNA, and protein methylation. It has been found beneficial in the treatment of liver disease, osteoarthritis, and particularly depression. However, SAMe's therapeutic potential is limited by low bioavailability due to poor permeability and extensive liver metabolism. This study sought to improve SAMe's bioavailability by encapsulating it in inulin nanoparticles, utilizing a colon-targeted delivery system. Inulin, a prebiotic that promotes gut health by encouraging beneficial gut bacteria, is an ideal carrier for colon-specific drug delivery. Inulin nanoparticles were prepared using the desolvation method, incorporating sodium lauryl sulfate (SLS) for ion pairing with SAMe. The nanoparticles were spray-coated onto microcrystalline cellulose inert microspheres in a fluidized bed with Eudragit L30D-55 for colon-targeted release (Nanoparticle-In-Microparticles, NIMs). Pharmacokinetic studies in rats showed that encapsulating SAMe in inulin nanoparticles resulted in a significant three-fold increase in bioavailability compared to its pure form. This enhancement highlights the potential of inulin nanoparticles as an effective delivery system for SAMe, particularly in colon-targeted therapies.

Different types of cancers affect the gastrointestinal tract (GIT), starting from the oral cavity and extending to the colon. In general, most of the current research focuses on the systemic delivery of the therapeutic agents, which leads to undesired side effects and a limited enhancement in the therapeutic outcomes. As a result, localized delivery within gastrointestinal (GI) cancers is favorable in overcoming these limitations. However, the localized delivery via oral administration faces many challenges related to the complex structure of GIT (varied pH levels and transit times) as well as the harsh environment within tumor cells (hypoxia, efflux pumps, and acidity). To overcome these obstacles, nano-drug delivery systems (NDDs) have been designed and proved their potential by exploiting these challenges in favor of offering a specific delivery to the desired target. The current review begins with an overview of different GI cancers and their impact globally. Then, it discusses the current treatment approaches and their corresponding limitations. Additionally, the different challenges associated with localized drug delivery for GI cancers are summarized. Finally, the review discusses in detail the recent therapeutic and diagnostic applications of NDDs that have been conducted in oral, esophageal, gastric, colon, and liver cancers, aiming to offer valuable insights into the current and future state of utilizing NDDs for the local treatment of GI cancers.

Orally targeting nanostrategies of multiple nutraceuticals have attracted increasing attention in ulcerative colitis (UC) therapy for superior patient compliance, cost-effectiveness, and biocompatibility. However, the actual targeting delivery and bioefficacy of nutraceuticals are extremely restricted by their poor solubility, interior gastrointestinal retention, and base permeability. Herein, we developed controllable colon-targeting nanoparticles (NPs) composed of a quaternary ammonium chitosan (HTCC) shell and succinic acid-modified γ-cyclodextrin (SACD) core for precise UC treatment. Egg white-derived peptides (EWDP, typical food-derived peptides) could not only function as potential cross-linkers to induce the differential coassembly with the above biopolymers but also aid the hydrophobic curcumin (Cur) solubility as well as nutrition enhancers for oral synergism of colitis therapy. More specifically, NPs with higher EWDP coassembly efficiency exhibited better pH-sensitive colloidal tunability (e.g., smaller size, higher rigidity, and roughness) and robust nutraceuticals (EWDP/Cur) coloading capacity (24.0-33.2% ≫ 10%, pH 2.0-7.0). Compared with pure nutraceuticals, NPs exhibited excellent cellular absorption (almost 10 times) and oral bioavailability (4.19-5.05 times) enhancement via faster mucus permeation and macropinocytosis transport, indirectly regulating the systemic inflammatory response. The sustainable sequential release and targeted accumulation profiles of NPs directly facilitated the interactions with the colonic microenvironment, verified by the intestinal barrier recovery and gut microbiota restoration. Moreover, the critical role of amino acid metabolism reconfirmed the importance of EWDP coassembly efficiency in maintaining intestinal homeostasis. Overall, this study would provide a facile, quantitative, and versatile perspective into the programmable design of food-derived peptide (e.g., EWDP) coassembled nanoplatforms for oral targeted therapy of UC.

Protein corona (PC) formation confers novel biological properties to the original nanomaterial, impeding its uptake and targeting efficacy in cells and tissues. Although many studies discussing PC formation have focused on inert proteins that may inhibit the function of nanomaterials, some functional plasma proteins with intrinsic targeting capabilities can also be adsorbed to the surface of nanomaterials, with active ligand properties to improve the targeting ability. In this approach, nanomaterials are surface-engineered to promote the adsorption of specific functional plasma proteins that are directly targeted to transport nanomaterials to the target site. In this study, T10 peptide-modified liposomes were employed to construct an in situ transferrin (Tf) PC-mediated liposome carrying a hypoxia-sensitive chemotherapy drug (tirapazamine, TPZ) and a photosensitizer (indocyanine green, IR820). The water-soluble drug TPZ was encapsulated in mesoporous silica nanoparticles (MSNs) and coated with IR820 (IR)-loaded liposome. Lipid-coated MSNs can inhibit aggregation in the body and significantly reduce the rapid release of water-soluble drugs, resulting in improved system stability and sustained release. Upon entering the in vivo circulation, T10 bound specifically to Tf in plasma to form an in situ Tf liposome-PC complex with enhanced targeting efficacy compared to traditional ligand-modified active-targeting strategies. However, large-sized PC particles faced challenges in penetrating deep into tumor tissues. IR could kill tumors through photodynamic therapy (PDT) and elicit complementary antitumor effects with the hypoxia-sensitive drug TPZ. This study demonstrates the novel design of in situ PC-mediated multifunctional liposomes for hypoxia-activated chemotherapy combined with PDT, a promising approach to cancer therapy.

Prebiotics and probiotics are applied against multiple diseases including ionizing radiation-induced injury but their functions are not revealed enough. Here, we used a prebiotic, inulin hydrogels (IGs) to load multi-strain probiotics (MSPs) for protecting them from the gastrointestinal environment and improving their colonization in the gut; more importantly, they showed the synergistic effect against ionizing radiation-induced injury. Probiotics were embedded in a great number of channels of the IGs and used IGs as food. The MSP was composed of Clostridium butyricum (Cb), Bifidobacterium adolescentis (Ba), and Akkermansia muciniphila (Akk), which separately mainly produced butyl acid, acetic acid and lactic acid, and stimulated mucin proteins. Although the MSP showed higher effect against mouse radiation enteritis than the single probiotics and the similar effect to IGs, the IG/MSP-based synbiotic had the highest protection and improved many factors close to the normal levels, including animal physical activity, enteric barrier function, occludin and ZO-1 expressions, injury extension, the levels of pro-inflammatory factors (IL-6, TNF-α), gut microbiota, and short-chained fatty acids. Moreover, the synbiotic had strong protection against whole-body irradiation with high blood cell numbers, hemopoietic system recovery, and high levels of IL-3 and IL-10. IGs greatly synergized probiotics against ionizing radiation-induced injury.

Polylactic acid (PLA) is a biodegradable and bio-based polymer that has gained significant attention as an environmentally friendly alternative to traditional petroleum-based plastics. In clinical treatment, biocompatible and non-toxic PLA materials enhance safety and reduce tissue reactions, while the biodegradability allows it to breakdown over time naturally, avoiding a second surgery. With the emergence of nanotechnology and three-dimensional (3D) printing, medical utilized-PLA has been produced with more structural and biological properties at both micro and macro scales for clinical therapy. This review summarizes current applications of the PLA-based biomaterials in drug delivery systems, orthopedic treatment, tissue regenerative engineering, and surgery and medical devices, providing viewpoints regarding the prospective medical utilization.

Polyelectrolyte complexes (PECs) are polymeric structures formed by the self-assembly of oppositely charged polymers. Novel biomaterials based on PECs are currently under investigation as drug delivery systems, among other applications. This strategy leverages the ability of PECs to entrap drugs under mild conditions and control their release. In this study, we combined a novel and sustainably produced hemicellulose-rich lignosulphonate polymer (EH, negatively charged) with polyethyleneimine (PEI) or chitosan (CH, positively charged) and agar for the development of drug-releasing PECs. A preliminary screening demonstrated the effect of several parameters (polyelectrolyte ratio, temperature, and type of polycation) on PECs formation. From this, selected formulations were further characterized in terms of thermal properties, surface morphology at the microscale, stability, and ability to load and release methylene blue (MB) as a model drug. EH/PEI complexes had a more pronounced gel-like behaviour compared to the EH/CH complexes. Differential scanning calorimetry (DSC) results supported the establishment of polymeric interactions during complexation. Overall, PECs' stability was positively affected by low pH, ratios close to 1:1, and the addition of agar. PECs with higher EH content showed a higher MB loading, likely promoted by stronger electrostatic interactions. The EH/CH formulation enriched with agar showed the best sustained release profile of MB during the first 30 h in a pH-dependent environment simulating the gastrointestinal tract. Overall, we defined the conditions to formulate novel PECs based on a sustainable hemicellulose-rich lignosulphonate for potential applications in drug delivery, which promotes the valuable synergy between sustainability and the biomedical field.

This study aimed to advance the development of intestinal colon-coated sustained-release matrix tablets of metronidazole for diverticulitis treatment, employing the Quality by Design (QbD) methodology. Comprehensive Risk analysis and Risk evaluation were conducted to assess the potential risks associated with Critical Material Attributes (CMA) and Critical Process Parameters (CPP). Ishikawa diagram, color-coded risk classification and the Risk Priority Number (RPN) were used as tools for risk evaluation. A Design of Experiments (DoE) was executed using a fractional factorial design, incorporating five key factors derived from the Risk analysis and Risk evaluation. Two levels and a central point were established for each factor, resulting in 28 batches of coated tablets. The manufacturing process involved direct compression, followed by a coating process using pH-dependent or time-dependent polymers. Characterization and dissolution studies were conducted on all batches, and the obtained results underwent analysis of variance (ANOVA). The findings demonstrated the robustness and reproducibility of both the direct compression and coating processes. Statistical analysis identified HPMC/chitosan ratio, blending time, coating polymer, and coating weight gain as factors significantly impacting drug release. A Design Space was established to delineate the interplay of these factors, offering insights into various combinations influencing drug release behavior. Thus, the design space for 10 % weight gain formulations includes a range of HPMC/CH ratios between 2.7-3 and mixing times between 10 and 12 min; for 20 % weight gain formulations it includes a range of HPMC/CH ratios up to 2 and mixing times between 10 and 16 min. Multiple Linear Regression between technological and biopharmaceutical variables were optimized facilitating scale-up operations. Batches with a 10 % weight increase and varied HPMC viscosity grades and coating polymers achieve ∼50 % drug release at 24 h; however, batches with a 20 % weight increase along, with either high proportions of HPMC and short blending times or low proportions of HPMC and longer blending times, achieve slow release of metronidazole. This study contributes to optimizing metronidazole colonic delivery systems, enhancing their potential efficacy in diverticulitis treatment.

Bioactive food ingredients contribute to the promotion and maintenance of human health and wellbeing. However, these functional ingredients often exhibit low biopotency after food processing or gastrointestinal transit. Well-designed oral delivery systems can increase the ability of bioactive food ingredients to resist harsh environments inside and outside the human body, as well as allow for controlled or triggered release of bioactives to specific sites in the gastrointestinal tract or other tissues and organs. This review presents the characteristics of common bioactive food ingredients and then highlights the barriers to their biopotency. It also discusses various oral delivery strategies and carrier types that can be used to overcome these biopotency barriers, with a focus on recent advances in the field. Additionally, the advantages and disadvantages of different delivery strategies are highlighted. Finally, the current challenges facing the development of food-grade oral delivery systems are addressed, and areas where future research can lead to new advances and industrial applications of these systems are proposed.

A colon-specific drug delivery system has great potential for the oral administration of colorectal cancer. However, the uncontrollable in vivo fate of liposomes makes their effectiveness for colonic location, and intratumoral accumulation remains unsatisfactory. Here, an oral colon-specific drug delivery system (CBS-CS@Lipo/Oxp/MTZ) was constructed by covalently conjugating Clostridium butyricum spores (CBS) with drugs loaded chitosan (CS)-coated liposomes, where the model chemotherapy drug oxaliplatin (Oxp) and anti-anaerobic bacteria agent metronidazole (MTZ) were loaded. Following oral administration, CBS germinated into Clostridium butyricum (CB) and colonized in the colon. Combined with colonic specifically β-glucosidase responsive degrading of CS, dual colon-specific release of liposomes was achieved. And the accumulation of liposomes at the CRC site furtherly increased by 2.68-fold. Simultaneously, the released liposomes penetrated deep tumor tissue via the permeation enhancement effect of CS to kill localized intratumoral bacteria. Collaborating with blocking the translocation of intestinal pathogenic bacteria from lumen to tumor with the gut microbiota modulation of CB, the intratumoral pathogenic bacteria were eliminated fundamentally, blocking their recruitment to immunosuppressive cells. Furtherly, synchronized with lipopolysaccharide (LPS) released from MTZ-induced dead Fusobacterium nucleatum and the tumor-associated antigens produced by Oxp-caused immunogenic dead cells, they jointly enhanced tumor infiltration of CD8+ T cells and reactivated robust antitumor immunity.

This chapter presents an overview of the emerging strategies to address the unmet needs in the management of inflammatory bowel diseases (IBD). IBD poses significant challenges, as over half of patients experience disease progression despite interventions, leading to irreversible complications, and a substantial proportion do not respond to existing therapies, such as biologics. To overcome these limitations, we describe a diverse array of novel therapeutic approaches. In the area of immune homeostasis restoration, the focus is on targeting cytokine networks, leukocyte trafficking, novel immune pathways, and cell therapies involving regulatory T cells and mesenchymal stem cells (MSC). Recognizing the critical role of impaired intestinal barrier integrity in IBD, we highlight therapies aimed at restoring barrier function and promoting mucosal healing, such as those targeting cell proliferation, tight junctions, and lipid mediators. Addressing the challenges posed by fibrosis and fistulas, we describe emerging targets for reversing fibrosis like kinase and cytokine inhibitors and nuclear receptor agonists, as well as the potential of MSC for fistulas. The restoration of a healthy gut microbiome, through strategies like fecal microbiota transplantation, rationally defined bacterial consortia, and targeted antimicrobials, is also highlighted. We also describe innovative approaches to gut-targeted drug delivery to enhance efficacy and minimize side effects. Reinforcing these advancements is the critical role of precision medicine, which emphasizes the use of multiomics analysis for the discovery of biomarkers to enable personalized IBD care. Overall, the emerging landscape of therapeutic opportunities for IBD holds great potential to surpass the therapeutic ceiling of current treatments.

Modified biopolymers that are based on prebiotics have been found to significantly contribute to immunomodulatory events. In recent years, there has been a growing use of modified biomaterials and polymer-functionalized nanomaterials in the treatment of various tumors by activating immune cells. However, the effectiveness of immune cells against tumors is hindered by several biological barriers, which highlights the importance of harnessing prebiotic-based biopolymers to enhance host defenses against cancer, thus advancing cancer prevention strategies. Inulin, in particular, plays a crucial role in activating immune cells and promoting the secretion of cytokines. Therefore, this mini-review aims to emphasize the importance of inulin in immunomodulatory responses, the development of inulin-based hybrid biopolymers, and the role of inulin in enhancing immunity and modifying cell surfaces. Furthermore, we discuss the various approaches of chemical modification for inulin and their potential use in cancer treatment, particularly in the field of cancer immunotherapy.

Breast cancer therapy has significantly advanced by targeting the programmed cell death-ligand 1/programmed cell death-1 (PD-L1/PD-1) pathway. BMS-202 (a smallmolecule PD-L1 inhibitor) induces PD-L1 dimerization to block PD-1/PD-L1 interactions, allowing the T-cell-mediated immune response to kill tumor cells. However, immunotherapy alone has limited effects. Clinically approved photodynamic therapy (PDT) activates immunity and selectively targets malignant cells. However, PDT aggravates hypoxia, which may compromise its therapeutic efficacy and promote tumor metastasis. We designed a tumor-specific delivery nanoplatform of liposomes that encapsulate the hypoxia-sensitive antitumor drug tirapazamine (TPZ) and the small-molecule immunosuppressant BMS. New indocyanine green (IR820)-loaded polyethylenimine-folic acid (PEI-FA) was complexed with TPZ and BMS-loaded liposomes via electrostatic interactions to form lipid nanocomposites. This nanoplatform can be triggered by near-infrared irradiation to induce PDT, resulting in a hypoxic tumor environment and activation of the prodrug TPZ to achieve efficient chemotherapy. The in vitro and in vivo studies demonstrated excellent combined PDT, chemotherapy, and immunotherapy effects on the regression of distant tumors and lung metastases, providing a reference method for the preparation of targeted agents for treating breast cancer.

The treatment of colorectal cancer is always a major challenge in the field of cancer research. The number of estimated new cases of colorectal cancer worldwide in 2020 is 1 148 515, and the estimated number of deaths is 576 858, revealing that mortality accounted for approximately half of the disease incidence. The development of new drugs and strategies for colorectal cancer treatment is urgently needed. Thermosensitive injectable hydrogel PDLLA-PEG-PDLLA (PLEL) loaded with cabazitaxel (CTX) is used to explore its anti-tumor effect on mice with orthotopic colorectal cancer. CTX/PLEL is characterized by a solution state at room temperature and a hydrogel state at physiologic temperature. The excipients MPEG-PCL and PDLLA-PEG-PDLLA have good biocompatibility and biodegradability. The simple material synthesis and preparation process renders this system cost-effective and more conducive to clinical transformation. An orthotopic colorectal cancer model is established by transplantation subcutaneous tumors onto the cecum of mice. According to the results of experiments in vivo, CTX/PLEL significantly inhibits orthotopic colorectal cancer and liver metastasis in mice. The results indicate that CTX/PLEL nanoparticle preparations have high security and excellent anti-tumor effects, and have great application potential in colorectal cancer therapy.

Inflammatory bowel disease (IBD) is a progressive and debilitating inflammatory disease of the gastrointestinal tract (GIT). Despite recent advances, precise treatment and noninvasive monitoring remain challenging.

Herein, we developed orally-administered, colitis-targeting and hyaluronic acid (HA)-modified, core-shell curcumin (Cur)- and cerium oxide (CeO2)-loaded nanoprobes (Cur@PC-HA/CeO2 NPs) for computed tomography (CT) imaging-guided treatment and monitoring of IBD in living mice.

Following oral administration, high-molecular-weight HA maintains integrity with little absorption in the upper GIT, and then actively accumulates at local colitis sites owing to its colitis-targeting ability, leading to specific CT enhancement lasting for 24 h. The retained NPs are further degraded by hyaluronidase in the colon to release Cur and CeO2, thereby exerting anti-inflammatory and antioxidant effects. Combined with the ability of NPs to regulate intestinal flora, the oral NPs result in substantial relief in symptoms. Following multiple treatments, the gradually decreasing range of the colon with high CT attenuation correlates with the change in the clinical biomarkers, indicating the feasibility of treatment response and remission.

This study provides a proof-of-concept for the design of a novel theranostic integration strategy for concomitant IBD treatment and the real-time monitoring of treatment responses.

Enzyme-triggered oral colon-specific drug delivery system (EtOCDDS1) can withstand the harsh stomach and small intestine environments, releasing encapsulated drugs selectively in the colon in response to colonic microflora, exerting local or systematic therapeutic effects. EtOCDDS boasts high colon targetability, enhanced drug bioavailability, and reduced systemic side effects. Polysaccharides are extensively used in enzyme-triggered oral colon-specific drug delivery systems, and its colon targetability has been widely confirmed, as their properties meet the demand of EtOCDDS. Polysaccharides, known for their high safety and excellent biocompatibility, feature modifiable structures. Some remain undigested in the stomach and small intestine, whether in their natural state or after modifications, and are exclusively broken down by colon-resident microbiota. Such characteristics make them ideal materials for EtOCDDS. This article reviews the design principles of EtOCDDS as well as commonly used polysaccharides and their characteristics, modifications, applications and specific mechanism for colon targeting. The article concludes by summarizing the limitations and potential of ETOCDDS to stimulate the development of innovative design approaches.

Recent advancements in genomics, transcriptomics, and metabolomics have significantly advanced our understanding of the human gut microbiome and its impact on the efficacy and toxicity of anti-cancer therapeutics, including chemotherapy, immunotherapy, and radiotherapy. In particular, prebiotics, probiotics, and postbiotics are recognized for their unique properties in modulating the gut microbiota, maintaining the intestinal barrier, and regulating immune cells, thus emerging as new cancer treatment modalities. However, clinical translation of microbiome-based therapy is still in its early stages, facing challenges to overcome physicochemical and biological barriers of the gastrointestinal tract, enhance target-specific delivery, and improve drug bioavailability. This review aims to highlight the impact of prebiotics, probiotics, and postbiotics on the gut microbiome and their efficacy as cancer treatment modalities. Additionally, we summarize recent innovative engineering strategies designed to overcome challenges associated with oral administration of anti-cancer treatments. Moreover, we will explore the potential benefits of engineered gut microbiome-modulating approaches in ameliorating the side effects of immunotherapy and chemotherapy.

Renal fibrosis is a progressive process associated with chronic kidney disease (CKD), contributing to impaired kidney function. Active constituents in traditional Chinese herbs, such as emodin (EMO) and asiatic acid (AA), exhibit potent anti-fibrotic properties. However, the oral administration of EMO and AA results in low bioavailability and limited kidney accumulation. Additionally, while oral probiotics have been accepted for CKD treatment through gut microbiota modulation, a significant challenge lies in ensuring their viability upon administration. Therefore, our study aims to address both renal fibrosis and gut microbiota imbalance through innovative co-delivery strategies.

In this study, we developed yeast cell wall particles (YCWPs) encapsulating EMO and AA self-assembled nanoparticles (NPYs) and embedded them, along with Lactobacillus casei Zhang, in chitosan/sodium alginate (CS/SA) microgels. The developed microgels showed significant controlled release properties for the loaded NPYs and prolonged the retention time of Lactobacillus casei Zhang (L. casei Zhang) in the intestine. Furthermore, in vivo biodistribution showed that the microgel-carried NPYs significantly accumulated in the obstructed kidneys of rats, thereby substantially increasing the accumulation of EMO and AA in the impaired kidneys. More importantly, through hitchhiking delivery based on yeast cell wall and positive modulation of gut microbiota, our microgels with this synergistic strategy of therapeutic and modulatory interactions could regulate the TGF-β/Smad signaling pathway and thus effectively ameliorate renal fibrosis in unilateral ureteral obstruction (UUO) rats.

In conclusion, our work provides a new strategy for the treatment of renal fibrosis based on hitchhiking co-delivery of nanodrugs and probiotics to achieve synergistic effects of disease treatment and targeted gut flora modulation.

Nanomedicine has been extensively explored for therapeutic and diagnostic applications in recent years, owing to its numerous advantages such as controlled release, targeted delivery, and efficient protection of encapsulated agents. Integration of microneedle technologies with nanomedicine has the potential to address current limitations in nanomedicine for drug delivery including relatively low therapeutic efficacy and poor patient compliance and enable theragnostic uses. In this Review, we first summarize representative types of nanomedicine and describe their broad applications. We then outline the current challenges faced by nanomedicine, with a focus on issues related to physical barriers, biological barriers, and patient compliance. Next, we provide an overview of microneedle systems, including their definition, manufacturing strategies, drug release mechanisms, and current advantages and challenges. We also discuss the use of microneedle-mediated nanomedicine systems for therapeutic and diagnostic applications. Finally, we provide a perspective on the current status and future prospects for microneedle-mediated nanomedicine for biomedical applications.

The abundance of Fusobacterium nucleatum (F. nucleatum) is highly associated with the development and poor prognosis of colorectal cancer (CRC), which is regarded as a promising target for CRC. However, until now, the novel strategy to clear F. nucleatum in the colon and CRC has not been well proposed. Herein, a probiotic strain Enterococcus faecium (E. faecium, EF47) is verified to secrete various organic acids and bacteriocins to exert superior antimicrobial activity towards F. nucleatum. However, the oral delivery of EF47 is affected by the complex digestive tract environment, so we design the hyaluronic acid-inulin (HA-IN) coated EF47 for colon-targeted delivery to fight F. nucleatum. IN can protect EF47 from the harsh gastrointestinal tract environment and is degraded specifically in the colon, acting as prebiotics to further promote the proliferation of EF47. The exposed HA can also enhance the targeting effect to the tumor area via the interaction with the CD44 receptor on the tumor cells, which is confirmed to increase the adhesive ability in tumor tissues and inhibit the growth of F. nucleatum. Therefore, this colon-targeted delivery system provides a novel platform to realize high-activity and adhesive delivery of probiotics to assist the therapeutic efficiency of CRC.

Colorectal cancer (CRC) is a common malignant tumor, and traditional treatments include surgical resection and radiotherapy. However, local recurrence, distal metastasis, and intestinal obstruction are significant problems. Oral nano-formulation is a promising treatment strategy for CRC. This study introduces physiological and environmental factors, the main challenges of CRC treatment, and the need for a novel oral colon-targeted drug delivery system (OCDDS). This study reviews the research progress of controlled-release, responsive, magnetic, targeted, and other oral nano-formulations in the direction of CRC treatment, in addition to the advantages of oral colon-targeted nano-formulations and concerns about the oral delivery of related therapeutic agents to inspire related research.

The intestine is essential for the modulation of nutrient absorption and the removal of waste. Gut pathologies, such as cancer, inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and celiac disease, which extensively impact gut functions, are thus critical for human health. Targeted drug delivery is essential to tackle these diseases, improve therapy efficacy, and minimize side effects. Recent strategies have taken advantage of both active and passive nanocarriers, which are designed to protect the drug until it reaches the correct delivery site and to modulate drug release via the use of different physical-chemical strategies. In this systematic review, we present a literature overview of the different nanocarriers used for drug delivery in a set of chronic intestinal pathologies, highlighting the rationale behind the controlled release of intestinal therapies. The overall aim is to provide the reader with useful information on the current approaches for gut targeting in novel therapeutic strategies.

Cancer stands as the second leading cause of death in the United States (US). Most chemotherapeutic agents exhibit severe adverse effects that are attributed to exposure of drugs to off-target tissues, posing a significant challenge in cancer therapy management. In recent years, inulin, a naturally occurring prebiotic fiber has gained substantial attention for its potential in cancer treatment owing to its multitudinous health values. Its distinctive structure, stability, and nutritional properties position it as an effective adjuvant and carrier for drug delivery in cancer therapy. To address some of the above unmet clinical issues, this review summarizes the recent efforts towards the development of inulin-based nanomaterials and nanocomposites for healthcare applications with special emphasis on the multifunctional role of inulin in cancer therapy as a synergist, signaling molecule, immunomodulatory and anticarcinogenic molecule. Furthermore, the review provides a concise overview of ongoing clinical trials and observational studies associated with inulin-based therapy. In conclusion, the current review offers insights on the significant role of inulin interventions in exploring its potential as a therapeutic agent to treat cancer.

In recent years, inulin has gained much attention as a promising multifunctional natural biopolymer with numerous applications in drug delivery, prebiotics, and therapeutics. It reveals a multifaceted biopolymer with transformative implications by elucidating the intricate interplay between inulin and the host, microbiome, and therapeutic agents. Their flexible structure, exceptional targetability, biocompatibility, inherent ability to control release behavior, tunable degradation kinetics, and protective ability make them outstanding carriers in healthcare and biomedicine. USFDA has approved Inulin as a nutritional dietary supplement for infants. The possible applications of inulin in biomedicine research inspired by nature are presented. The therapeutic potential of inulin goes beyond its role in prebiotics and drug delivery. Recently, significant research efforts have been made towards inulin's anti-inflammatory, antioxidant, and immunomodulatory properties for their potential applications in treating various chronic diseases. Moreover, its ability to reduce inflammation and modulate immune responses opens new avenues for treating conditions such as autoimmune disorders and gastrointestinal ailments. This review will attempt to illustrate the inulin's numerous and interconnected roles, shedding light on its critical contributions to the advancement of healthcare and biomedicine and its recent advancement in therapeutics, and conclude by taking valuable insights into the prospects and opportunities of inulin.

A brain-targeting nanodelivery system has been a hot topic and has undergone rapid progression. However, due to various obstacles such as the intestinal epithelial barrier (IEB) and the blood-brain barrier (BBB), few nanocarriers can achieve brain-targeting through oral administration. Herein, an intelligent oral brain-targeting nanoparticle (FTY@Man NP) constructed from a PLGA-PEG skeleton loaded with fingolimod (FTY) and externally modified with mannose was designed in combination with a glucose control strategy for the multitarget treatment of Alzheimer's disease (AD). The hydrophilic and electronegative properties of the nanoparticle facilitated its facile penetration through the mucus barrier, while the mannose ligand conferred IEB targeting abilities to the nanoparticle. Subsequently, glycemic control allowed the mannose-integrated nanoparticle to hitchhike the glucose transporter 1 (GLUT1) circulation across the BBB. Finally, the released FTY modulated the polarity of microglia from pro-inflammatory M1 to anti-inflammatory M2 and normalized the activated astrocyte, enhancing the clearance of toxic protein Amyloid-β (Aβ) while alleviating oxidative stress and neuroinflammation. Notably, both in vitro and in vivo results have consistently demonstrated that the oral administration of FTY@Man NP could effectively traverse the multiple barriers, thereby exerting significant therapeutic effects. This breakthrough holds the promise of realizing a highly effective orally administered treatment for AD.