Nanomedicine for Oral Delivery: Strategies to Overcome the Biological Barriers

Abstract

Oral drug delivery is highly desirable for medical intervention due to its convenience, patient adherence, and non‐invasiveness. Despite significant efforts, the successful oral delivery of therapeutics and prophylactics has been largely hindered by biological barriers that limit bioavailability. Researchers have since turned to nanoparticles as promising delivery vehicles that offer tunable properties to protect therapeutic payloads and enhance transport across these barriers. In addition to material optimization and delivery strategies, biomimetic designs—particularly those inspired by viruses—have significantly advanced the field, leveraging natural mechanisms to penetrate mucosal layers through size, charge, and enzymatic functions. This review examines the key physiological challenges limiting oral drug absorption, including the harsh gastric environment, the mucosal layer, and the polarized epithelial barrier. Recent preclinical advancements are then highlighted in nanoparticle engineering aimed at overcoming these barriers and improving bioavailability. Continued innovation in oral nanomedicine holds immense potential to revolutionize treatment paradigms, enhancing both therapeutic efficacy and patient outcomes worldwide.

Oral delivery is a preferred administration route for many clinical applications, valued for its strong patient compliance. In this review, how nanoparticles are engineered and deployed to overcome the gastrointestinal barriers that impede clinical translation of oral delivery formulations is examined.

1. Introduction

The route of administration is a critical factor in developing novel therapeutics and prophylactics, with oral delivery being one of the most desirable options across a variety of applications.^{[ 1 ]} The choice of administration route encompasses a myriad of downstream factors for consideration, ranging from patient compliance (comfort, reliability, and convenience) to biomolecular challenges (formulation stability, biological barriers, and degradation risks). Oral delivery is highly favorable for patient compliance as it is fast, painless, and convenient. Oral formulations, typically in pill or liquid form, can be taken within seconds at home and can be easy to stored and transported. In contrast, alternative routes such as injections or infusions often require medical appointments, can be painful or embarrassing, and may discourage adherence to protocols.^{[ 2 ]} This is particularly the case for diabetics, who would see a quality of life improvement with a reliably bioavailable form of orally delivered insulin instead of frequent injections.^{[ 3 ]} Additionally, familiarity with oral medications further enhances patient comfort and acceptance.

Despite these advantages, oral delivery has not been a reliable option due to complex biological barriers that hinder systemic bioavailability and reduce efficacy at the disease site.^{[ 4 ]} Achieving systemic bioavailability requires medications to withstand the harsh gastric environment, penetrate the mucosal layer, and traverse the gut epithelium into the bloodstream. This gut‐blood axis is further complicated by the polarized nature and diversity of the cell types that comprise it.^{[ 5 ]} Even when oral delivery provides the most direct access to the disease site, as in inflammatory bowel disease (IBD) or colorectal cancer, the complexity of the gastrointestinal tract often limits treatment efficacy.^{[ 6} , ^{7 ]} Drugs delivered using conventional oral delivery systems, such as capsules or tablets, can exhibit limited bioavailability and suboptimal distribution. These challenges have restricted the use of oral medication and limited the development of effective oral vaccine formulations.^{[ 8 ]} To overcome these limitations, permeation enhancers, such as bile salts, chitosan, and surfactants, have been utilized to enhance the intestinal absorption of oral medications.^{[ 9 ]}

Nanoparticles have emerged as promising delivery vehicles across multiple routes of administration, including for oral applications.^{[ 10 ]} Their tunable characteristics—including size, material composition, and functionalization—allow them to carry diverse payloads while interacting effectively with biological systems. Decades of research with alternate routes of administration, often with similar therapeutics, have led to highly established platforms that can be optimized or adjusted for oral delivery. This flexibility enables the selection of the best therapeutic agent without being restricted by its intrinsic bioavailability. Nanoparticles are particularly valuable for highly sensitive molecules like mRNA, which require protective carriers for stability and efficient delivery.^{[ 11 ]} Recent research efforts have focused on engineering nanoparticles to overcome the inherent barriers of oral delivery, particularly by optimizing their charge, size, and surface functionalization.^{[ 12 ]} Many strategies draw inspiration from nature, leveraging biomimetic designs modeled after organisms such as viruses, which excel at penetrating the mucosal barrier.^{[ 13 ]}

In this review, we evaluate the current state of oral medicines (Figure 1 ). Next, we examine the biological mechanisms that impede the oral delivery of therapeutics and prophylactics. We then explore nanomedicine strategies that can be used to overcome these challenges. Finally, we analyze recent advancements in oral nanomedicine, highlighting promising developments in the field and providing insight into future investigations.

Figure 1.

Nanomedicine for oral delivery. Nanoparticles can be engineered to encapsulate various therapeutic payloads for oral administration. However, the gastrointestinal tract presents several barriers to effective delivery, including stomach acid, the mucosal layer, and a polarized epithelial cell barrier. Overcoming these challenges would enable nanoparticles to excel at treating both local gastrointestinal diseases as well as other systemic conditions. Created with BioRender.

2. The Barriers to Oral Delivery and Traditional Strategies

Oral drug delivery is complicated by the unfavorable physiological characteristics of the gastrointestinal tract.^{[ 4} , ¹⁴ , ^{15 ]} For systemic drug delivery applications, a drug carrier must generally pass through the oral cavity, esophagus, stomach, and finally into the small intestine, where the extensive surface area provided by villi and microvilli makes it a suitable site for drug absorption. At this point, rapid diffusion across the local mucosa is required to avoid excretion. Lastly, the drug carrier must traverse or release its payload across a polarized epithelial cell barrier. The number or nature of these barriers is dependent on factors such as the health status of the patient, further increasing the challenge of this administration route. Additionally, the characteristics and delivery requirements of the desired payload can impact the design features of the drug carrier. For example, drugs with low solubility and/or low permeability may necessitate that their carriers be able to overcome more biological barriers than others. Over the years, various strategies have been developed to overcome these challenges.^{[ 16 ]}

The stomach presents major challenges to unprotected pharmaceuticals due to its highly acidic environment (pH 1.0–2.5), which eliminates acid‐labile drugs, and enzymes like pepsin, which degrade protein‐based drugs. Solid dosage forms are frequently used for the oral delivery of pharmaceuticals due to their ease of manufacture and administration.^{[ 17} , ¹⁸ , ^{19 ]} It allows pharmaceutical companies to provide drugs in predetermined dosages, allowing easy self‐administration and patient compliance. These drug forms can also be made with more chemical and physical stability, allowing for the logistical benefits of easy storage. Furthermore, the pharmaceutical industry is familiar with manufacturing solid dosage forms, providing ease in drug translation. There are several types of solid dosage forms with many readily soluble drugs stored in a stable powdered form to either be compressed into tablets or encapsulated in capsules. However, formulations with poor aqueous solubility may be formulated within soft gelatin capsules.^{[ 20 ]} Acid labile drugs often require a delivery strategy involving enteric coatings, where release is triggered only after passing through the stomach and entering the small intestine.^{[ 21} , ^{22 ]} Enteric coatings utilize a polymer that is insoluble in the acidic conditions of the stomach but soluble in the more neutral conditions of the small intestine. The utilization of enteric coatings for oral delivery has been successful in numerous applications. Common enteric coating materials include polymethacrylates, cellulose derivatives, and polyvinyl derivatives.^{[ 23 ]} Some enteric coatings can also function as acid modifiers, incorporating citric acid to create a localized acidic environment that inhibits the activity of certain proteases.^{[ 24 ]} However, enteric coatings were found to impact drug pharmacodynamics in a study investigating the effect of enteric‐coated aspirin in patients with type 2 diabetes.^{[ 25 ]} Researchers found greater intersubject variability, with some patients experiencing a significant decrease in drug absorption. Similar findings were reported in studies on enteric‐coated aspirin given to healthy volunteers.^{[ 26 ]}

The small intestines are coated by a single, loose mucosal barrier primarily composed of mucins secreted by goblet cells, while the colon has an additional inner layer of cell‐surface‐associated mucins, both of which pose a significant barrier to oral drug delivery.^{[ 27 ]} The pores of the mucus in the gastrointestinal tract are ≈100–200 nm in diameter, generating a size limiting feature for drug carriers. Mucus also carries a natural negative charge due to the presence of carboxyl and sulfate groups in its O‐linked oligosaccharide chains.^{[ 28} , ^{29 ]} This makes for an interesting challenge, as negatively charged drug carriers may repel these charges and penetrate the mucus but struggle to initially adhere or attach to the mucus. A strategy to overcome the mucosal barrier involves directly modifying the structure of the mucus lining.^{[ 30 ]} Some tactics explored for mucin disruption involve the use of either thiol groups to cleave disulfide bonds,^{[ 31 ]} or mucolytic enzymes, such as cysteine proteases can cleave amide bonds in the less glycosylated mucin regions.^{[ 32} , ^{33 ]}

Oral drug delivery for systemic applications requires transcellular transport across epithelial barriers, which are formed through tight junction protein complexes, adherens junctions, and desmosomes.^{[ 34 ]} These connective complexes are selective for size and charge, which limits the paracellular transport of ions and large molecules.^{[ 35 ]} There are a variety of cell types that make up this epithelial cell barrier, but enterocytes are the most prevalent cell type in the small intestine and are also an optimal target for oral drug delivery.^{[ 36 ]} Microfold (M) cells represent a minor proportion of intestinal epithelial cells but are also appealing targets for oral drug delivery due to their proficiency with macromolecule transcytosis.^{[ 37 ]} M cells are located within the follicle‐associated epithelium of Peyer's patches. Goblet cells, which secrete mucin proteins to form the intestinal mucus layer, also represent a potential target for oral drug delivery.^{[ 38} , ^{39 ]} Within the past couple of decades, researchers have turned to innovative biomedical nanotechnology as a possible solution for addressing the barriers to oral drug delivery.

3. Biomedical Nanotechnology

Nanomedicine applies nanomaterials for medical purposes, including vaccination, therapy, and diagnosis.^{[ 10} , ^{40 ]} By harnessing the unique biological and physical properties of nanomaterials, nanomedicine addresses challenges faced by conventional free drugs. However, its therapeutic potential is constrained by factors such as clearance by the kidney or liver, uptake by phagocytic cells, specific cellular binding, and biological barriers. Nanoparticles can be specifically optimized to address these limitations, enabling increased payload stability, prolonged circulation time, site‐specific targeting, and more efficient transport across biological barriers. Cell‐specific targeting can be achieved by functionalization with active targeting agents. Proteins, peptides, and polymers have all been well‐researched in promoting the advancement of targeted nanomedicine. The ability of nanoparticles to facilitate site‐specific targeting holds particular promise in the medicinal world, broadening the applications of nanomedicine.^{[ 41} , ^{42 ]} Targeted nanoparticle drug delivery is important in increasing the efficacy of the treatment while minimizing potentially harmful adverse effects. Nanomaterials can be generalized into several different classes, such as inorganic, organic, and polymeric.^{[ 43 ]} The selection of nanoparticle material depends on the application, with each nanomaterial boasting its own advantages and capabilities.

Inorganic nanoparticles, such as those based on gold and iron, can be synthesized in a variety of sizes and structural geometries, increasing their range of use.^{[ 10 ]} Inorganic nanomaterials can boast unique electrical and magnetic properties, oftentimes making them suitable for diagnostic purposes. Gold nanoparticles, for example, can be synthesized in various geometries that determine their efficacy as a diagnostic tool. Iron oxide nanoparticles share similar photothermal properties as well. Other inorganic nanoparticles, like mesoporous silica nanoparticles (MSNs), have been well‐explored for their efficiency in drug and gene delivery, as they can encapsulate proteins, peptides, nucleic acids, and small molecules for diverse applications.^{[ 44 ]} MSNs are characterized by a highly tunable surface, where charge and pore size can be manipulated, allowing diverse surface functionalization.

The use of organic biomaterials in nanomedicine has grown significantly over the past few decades.^{[ 45} , ^{46 ]} Organic biomaterials have enabled highly efficient oral and injectable nanoparticle delivery and opened doors to less established delivery routes. Liposomes are simple nanoparticles composed of a phospholipid bilayer with an aqueous core capable of encapsulating hydrophobic and hydrophilic.^{[ 10 ]} This class of nanoparticles has experienced immense growth, particularly regarding additional surface modifications for enhanced delivery, and inspired the development of other lipid‐based nanoparticles, such as modern lipid nanoparticles (LNPs). LNPs are characterized by four major components: cholesterol, a phospholipid, a polyethylene glycol (PEG)‐lipid conjugate, and an ionizable or cationic lipid.^{[ 46 ]} The ionizable or cationic lipid allows for encapsulating negatively charged nucleic acids, such as small interfering RNA (siRNA) and messenger RNA (mRNA), as well as facilitating endosomal escape within the cell.^{[ 47} , ^{48 ]} LNPs are utilized in mRNA‐based COVID‐19 vaccine formulations, demonstrating their efficacy in clinical settings. Recently, cell membrane coating nanotechnology has gained interest for its applications in nanomedicine.^{[ 49 ]} Natural cellular membranes can be harvested and used to coat synthetic nanoparticles, creating a biomimetic nanoparticle platform. These nanoparticles effectively mimic the properties of their source cells, leading to a wide range of applications. These cell membranes can be functionalized, either through genetic engineering or lipid‐insertion mechanisms, to further extend the application of cell membrane coating to enhance targeted nanoparticle delivery.^{[ 50} , ^{51 ]}

Polymeric nanoparticles have attracted significant attention as drug delivery platforms due to their controllable design and various functionalities.^{[ 52 ]} Poly(lactic‐co‐glycolic acid) (PLGA) is a biodegradable copolymer approved by the FDA for drug delivery.^{[ 53} , ^{54 ]} PLGA nanoparticles are easily functionalized for targeted delivery. PEG is a hydrophilic polymer that can be used to coat nanoparticles, a process often referred to as PEGylation.^{[ 55 ]} PEGylated PLGA nanoparticles resist interaction with biological components in the bloodstream, increasing circulation time. PEGylation has drawn concern, however, due to the formation of anti‐PEG antibodies in the body, which reduces the efficacy of the platform for systemic delivery.^{[ 56 ]} Chitosan, another biodegradable and FDA‐approved polymer, is used for a variety of nanomedicine applications.^{[ 57 ]} Chitosan has a positively charged surface with functional groups that can be modified for targeting. The positive charge enables increased mucoadhesion, making chitosan an excellent candidate for non‐parenteral drug administration.

Understanding the varying toxicities of nanomaterials is important in determining the best platform for specific applications. The immune system is often responsible for the clearance of nanoparticles, which can result in inflammation‐based toxicities.^{[ 10 ]} Nanoparticle properties such as charge affect toxicity as well, as the positive charge of cationic nanoparticles can damage or disrupt the cell membrane. Other surface material properties, such as the inclusion of PEG for increased nanoparticle residence, can lead to adverse reactions like anaphylaxis.^{[ 58 ]} Metal nanoparticles can release harmful ions during degradation that create high levels of oxidative stress. These various toxicities create several challenges when translating nanomedicine research from the laboratory to the clinic. There are many types of nanomaterials currently approved by the FDA for clinical use.^{[ 59 ]} A common issue faced by many nanomedicines is the lack of specific targeting, leading to potential nanoparticle accumulation in healthy tissue.^{[ 60 ]} Many strategies are being explored for increased specificity, such as active and passive targeting. Besides biological challenges, general issues like the lack of an efficient assessment of nanomedicine safety can also complicate the translation process. Even common drugs, like paclitaxel, become difficult to assess when combined with complex nanomaterials. Manufacturing difficulties are prevalent in nanomedicine as well, since high nanoparticle complexity can lead to more significant challenges in large‐scale production.^{[ 61 ]} It is important to consider these potential issues in the early stages of research to leave the door open to potential clinical translation, especially in developing oral nanomedicine delivery systems.

4. Application of Nanoparticles for Oral Medicine

4.1. Systemic Applications

4.1.1. Diabetes

Diabetes mellitus is a class of conditions characterized by hyperglycemia due to a lack of sufficient insulin production (type I) or insulin resistance/relative deficiency (type II).^{[ 62 ]} Oral delivery is a highly favorable route of administration for diabetes patient compliance, as consistent application is crucial for treatment.^{[ 12} , ^{63 ]} The development of a reliable oral insulin formulation has become a top priority for nanomedicine researchers, representing a significant portion of work in the field.^{[ 64} , ^{65 ]} However, oral administration presents significant challenges, including the acidic gastric environment, the mucosal lining of the intestines, and the polarized epithelial cells that form a barrier to the bloodstream. Recently, progress has been made in utilizing nanoparticles to protect payloads like insulin and facilitate their delivery across these barriers.^{[ 66 ]}

PEG has been extensively studied for oral delivery due to its hydrophilicity and muco‐inert nature.^{[ 67} , ^{68 ]} However, the addition of PEG to a nanoparticle can also inhibit cellular uptake once past the mucus layer. In a recent study to address this, researchers optimized the conjugation of PEG to PLGA nanoparticles via a hydrazone bond to achieve mucopenetration without compromising cellular uptake.^{[ 69 ]} The hydrazone bond remained stable in jejunal fluid but hydrolyzed in acidic conditions at the enterocyte surface, enabling PEG shedding after mucopenetration to enhance cellular uptake. Administration of these nanoparticles loaded with insulin to type I diabetic rats resulted in a 40% reduction in blood glucose levels at a 100 IU kg⁻¹ insulin dose. However, subcutaneous injection of insulin at 5 IU kg⁻¹ was still more effective, reducing blood glucose by ≈70% within 2 h.

Efforts to enhance oral insulin administration have led to the exploration of zwitterionic nanoparticles, which possess both positively and negatively charged functional groups but with an overall neutral surface charge.^{[ 70} , ⁷¹ , ^{72 ]} The hydrophilic nature and non‐fouling properties of zwitterionic nanoparticles enable them to penetrate mucosal barriers. One promising polymer is polycarboxybetaine (PCB), which has been conjugated with a lipid to form zwitterionic micelles for insulin delivery.^{[ 73 ]} These micelles leverage betaine's zwitterionic profile and hydrophilic nature to penetrate the hydrophobic regions of mucus. In vitro studies using porcine stomach mucus demonstrated that the zwitterionic micelles exhibited a mean square displacement 12 times greater than PEG‐containing polysorbate 80 micelles. Additionally, betaine facilitates epithelial cell uptake and transcytosis via proton‐assisted amino acid transporter 1. To assess the formulations' ability to deliver insulin, mice with induced type I diabetes were treated with the micelles containing 20 IU kg⁻¹ of insulin via the ileum. This resulted in a significant blood glucose reduction, comparable to subcutaneous injection of 5 IU kg⁻¹ of insulin. However, oral gavage of the same formulation showed reduced efficacy, likely due to nanoparticle degradation in the gastrointestinal tract. To address this, researchers developed a dry powder formulation encapsulated within a gelatin capsule coated with the enteric polymer Eudragit L100‐55 to protect against stomach acid. This approach restored insulin efficacy, and the capsule formulation at an insulin dose of 20 IU kg⁻¹ was able to significantly reduce blood glucose levels, akin to the mice treated with insulin subcutaneously.

Inspired by viruses, which often exhibit a balanced surface charge due to a mix of positive and negative amino acids, researchers have designed virus‐mimetic mesoporous silica nanoparticles for oral insulin delivery.^{[ 74 ]} The nanoparticles were surface‐modified with cationic KLPVM peptides and anionic glutaric anhydride to achieve an overall neutral charge, mimicking viral mucopenetration. The KLPVM peptide further facilitated uptake via its cell‐penetrating properties. To demonstrate their platform in vivo, the group administered type 1 diabetic rats with the nanoformulation or free insulin at 100 IU kg⁻¹ via intrajejunal injection. Nanoparticle‐based insulin delivery via intrajejunal injection reduced blood glucose by 56% within 3 h, outperforming free insulin but not subcutaneous injection at 5 IU kg⁻¹, which achieved an 89% reduction. Another virus‐inspired approach utilized PLGA nanoparticles coated with both the R8 cell‐penetrating peptide and anionic phosphoserine via lipid‐PEG linkers (Figure 2 ).^{[ 75 ]} The overall neutral charge of the nanoparticle allowed it to penetrate the intestinal mucus layer. Upon arrival at the epithelial cell barrier, the phosphoserine underwent hydrolysis by intestinal alkaline phosphatase. This led to an overall positive charge via exposure of the R8 peptide, facilitating epithelial cell uptake and transcytosis. In vivo experiments with fasted type 1 diabetic rats showed that oral administration of the nanoformulation at 50 IU kg⁻¹ of insulin resulted in a 32% glucose reduction after 3 h. This surpassed the blood glucose reduction of orally administered free insulin but fell short of 5 IU kg⁻¹ insulin administered subcutaneously.

Figure 2.

Charge reversal as a strategy to bypass the mucus barriers. A) PLGA nanoparticles loaded with insulin are functionalized with both anionic phosphoserine (Pho) groups and cationic R8 peptide. The slightly negative surface charge facilitates efficient mucopenetration but is subsequently reversed due to the enzymatic cleavage of Pho from the nanoparticle surface. The positively charged nanoparticle is then able to be taken up by epithelial cells. B) The nanoparticles show significantly increased basolateral transport in a transwell co‐culture model. C) The nanoparticles carrying insulin can regulate blood glucose levels after oral administration. Adapted with permission.^{[ 75 ]} Copyright 2018, American Chemical Society.

A similar charge‐switching tactic was employed in another form with bovine serum albumin‐coated cationic liposomes for oral insulin delivery (Figure 3 ).^{[ 76 ]} The nanoparticle utilized its negatively charged protein corona to navigate through the mucus, which was then shed upon reaching the epithelium, exposing the cationic core for efficient transcytosis. Other nanocarriers utilize the bile acid pathway for insulin transport (Figure 4 ).^{[ 77 ]} For example, a deoxycholic acid‐modified nanocarrier was shown to cross the apical membrane via apical sodium‐dependent bile acid transporter‐mediated endocytosis and traverse the intracellular space and basolateral membrane by interacting with cytosolic ileal bile acid‐binding protein.

Figure 3.

Protein corona liposomes for mucopenetration and transcytosis. A) Bovine serum albumin (BSA) is adsorbed onto the surface of cationic liposomes to decrease their zeta potential and increase their hydrophilicity for mucopenetration after oral administration. As the nanoparticles traverse through the mucosal layer toward the epithelial layer, BSA is removed from the surface by enzymes until finally the nanoparticles can be transcytosed for systemic delivery of insulin. B) The protein‐coated cationic liposome (PcCL) formulation exhibits prolonged regulation of blood glucose levels after administration. Adapted with permission.^{[ 76 ]} Copyright 2019, Wiley‐VCH.

Figure 4.

Utilization of the bile acid pathway for epithelial transcytosis. A) Deoxycholic acid‐modified nanoparticles (DNPs) loaded with insulin enable uptake by intestinal epithelial cells via the apical sodium‐dependent bile acid transporter (ABST). After endosomal escape, the nanoparticles are transported to the basolateral domain via ileal bile acid‐binding protein (IBABP), where the payload can subsequently be discharged into the bloodstream. B) The DNP formulation facilitates prolonged systemic delivery of insulin. Adapted with permission.^{[ 77 ]} Copyright 2018, Elsevier.

Beyond mucopenetration, alternative strategies have been explored to deliver insulin through the intestinal epithelial layer without direct cellular uptake. One example focused on opening the tight junctions between epithelial cells.^{[ 78 ]} Researchers utilized anionic silica nanoparticles, which also have mucopenetration properties, to bind integrin receptors on intestinal epithelial cells, activating myosin light chain kinase and temporarily opening tight junctions. In type 1 diabetic mice, oral gavage administration of the silica nanoparticles, followed by oral delivery of 10 IU kg⁻¹ insulin in gel capsules (co‐loaded with a protease inhibitor and coated with Eudragit L100‐55) facilitated a decrease in relative blood glucose level. Additionally, the relative bioactivity of the 10 IU kg⁻¹ capsules was 23% in diabetic mice compared to a 1 U kg⁻¹ subcutaneous insulin dose. It was also found that the enhanced permeability was reversible, which is important for future clinical use. Other groups have researched different reversible mechanisms to open tight junctions for the delivery of insulin, including the utilization of chitosan‐based nanoparticles.^{[ 79} , ^{80 ]}

4.1.2. Cancer

Beyond diabetes, significant research efforts have been dedicated to developing oral nanoparticle delivery systems for systemic cancer treatment.^{[ 81} , ^{82 ]} Conventional cancer therapies, such as chemotherapy, are often restricted to intravenous injection, whereas oral administration would represent a more desirable option for improved patient compliance.^{[ 83 ]} Paclitaxel (PTX), a widely used chemotherapy drug for various cancer types, has been investigated for oral delivery using PEG due to its mucopenetration properties.^{[ 84} , ^{85 ]} Researchers synthesized a novel copolymer by combining a PEGylated construct with glycocholic acid, which was incorporated to enhance epithelial cell uptake by promoting transcytosis via the apical sodium‐dependent bile acid transporter pathway. An Fmoc motif enabled PTX association onto the copolymer, which was formed into micelles after synthesis. In a lung cancer rat model, orally administered micelles at 20 mg kg⁻¹ demonstrated similar tumor suppression after 12 days compared to intravenous Taxol at 10 mg kg⁻¹. However, it is important to note that oral nanoformulation was administered every two days, whereas Taxol was given every four days.

Zwitterionic polymers have also proven to be promising for the oral delivery of PTX. In one example, OPDEA was identified as a polyzwitterion with epithelial cell uptake and mucopenetration capabilities (Figure 5 ).^{[ 86 ]} OPDEA's neutral surface charge enables efficient mucopenetration, while its weak binding to cell membranes facilitates rapid cellular uptake and transcytosis. The researchers developed OPDEA‐block‐poly(ε‐caprolactone) (OPDEA‐PCL) micelles as a nanocarrier for PTX, enabling mucus penetration, epithelial absorption, and transepithelial transport. In an in vitro transwell model, OPDEA‐PCL exhibited faster penetration of a thick mucus layer than PEG‐PCL micelles. In an in situ perfusion study using a rat jejunum segment, OPDEA‐PCL micelles demonstrated 27 fold higher intestinal absorption compared to their PEG‐PCL counterparts. Furthermore, in vitro studies with Caco‐2 cells revealed accumulation of OPDEA‐PCL micelles in the endoplasmic reticulum and Golgi apparatus, indicating efficient transepithelial nanoparticle transport. In vivo, PTX‐loaded OPDEA‐PCL micelles administered orally at 20 mg kg⁻¹ significantly reduced tumor sizes in multiple murine tumor xenograft models. Systemic toxicity studies indicated no pathological damage to major organs, with kidney and liver function markers remaining unaffected.

Figure 5.

Polyzwitterionic micelles for the oral delivery of chemotherapeutics. A) The OPDEA‐PCL copolymer and PTX self‐assemble into non‐fouling micelles that are capable of efficient mucopenetration and subsequent epithelial transcytosis to the bloodstream for cancer therapy. B) In a transwell mucopenetration model, the OPDEA‐PCL micelles show enhanced transport to the basolateral chamber compared with a PEGylated control. C) The oral nanoformulation is effective at treating HepG2 xenografts (left) and HCC PDX tumors (right). Adapted with permission.^{[ 86 ]} Copyright 2022, Wiley‐VCH.

Chitosan is a cationic polysaccharide that has been explored for the oral delivery of therapeutic payloads due to its ability to open intestinal epithelial tight junctions, thereby facilitating transport across the epithelial barrier.^{[ 87 ]} In addition to enhancing permeability, chitosan's strong positive charge promotes mucoadhesion, increasing nanoparticle retention at the absorption site.^{[ 88} , ^{89 ]} Leveraging these properties, a research group recently developed a thiolated chitosan copolymer modified with polylysine, poly(lactide), and cysteine for PTX encapsulation.^{[ 90 ]} Polylysine further enhanced the positive charge to prolong mucus retention, poly(lactide) provided hydrophobicity for improved PTX encapsulation, and cysteine enhanced mucoadhesion and epithelial permeation. In an in vivo study, mice with hepatic tumors received oral administration of the drug‐containing nanocomplex at 20 mg kg⁻¹ PTX, resulting in significant reductions in tumor weight and volume compared to Taxol. Additional studies have also investigated chitosan‐based polymers for oral PTX delivery.^{[ 91 ]}

4.1.3. Infection and Dysbiosis

Nanomedicines may encounter gut microbiota when delivered orally, and thus their impact must be considered in this regard. Binding‐mediated cellular uptake is a strategy that has been explored to limit such negative effects. For example, nanoparticles were functionalized with glucose on their surface to facilitate sodium‐glucose linked transporter 1‐mediated endocytosis in the proximal small intestine for systemic antibiotic delivery to the lungs.^{[ 92 ]} The transporter molecule was found to be overexpressed in the proximal small intestine compared to the colon and large intestine, promoting targeted nanoparticle absorption. Since oral antibiotic delivery to the colon can lead to gut dysbiosis, targeting the small intestine and avoiding the colon is crucial. Mice orally administered with the glucosylated nanoparticles exhibited significantly increased absorption in the small intestine compared to the large intestine. In vivo experiments demonstrated that oral administration of the nanoparticles loaded with ampicillin at 40 mg kg⁻¹ resulted in significantly higher serum ampicillin concentrations compared to non‐glucosylated controls. Furthermore, oral administration of the glucosylated nanoformulation led to a 20.9 fold increase in serum ampicillin concentration after 4 h compared to free ampicillin.

Gut dysbiosis has been linked with gastrointestinal tract disorders such as ulcerative colitis and colorectal cancer.^{[ 93 ]} In such cases, oral nanomedicines to restore a healthy gut microbiome have been explored. These platforms are not required to penetrate the gut epithelium but instead are designed to target microbes in the lumen of the gastrointestinal tract. Several nanoparticle systems have been found to modulate the intestinal flora for anticancer treatments. 

4.2. Local Gastrointestinal Applications

4.2.1. Inflammatory Bowel Disease

IBD is characterized by chronic inflammation of the digestive tract and includes both Crohn's disease and ulcerative colitis.^{[ 94 ]} Crohn's disease can affect any part of the gastrointestinal tract with dispersed lesions.^{[ 95} , ^{96 ]} In contrast, ulcerative colitis is confined to the colon and is characterized by continuous lesion formation. Although the exact etiology of IBD remains unclear, it is associated with complex interactions among genetic, microbial, environmental, and immune factors. Over the past few decades, numerous therapies have been developed to treat IBD, which can be categorized into small molecules, peptides, and antibodies based on their structures.^{[ 97 ]} Aminosalicylates, like mesalazine, have been used for over 80 years to treat IBD by inhibiting the conversion of arachidonic acid to prostaglandins and leukotrienes, neutralizing reactive oxygen species (ROS), and increasing regulatory T cell infiltration in the colon.^{[ 98 ]} Oral corticosteroids, such as budesonide, have also been used for the treatment of IBD to inhibit the transcription of proinflammatory genes and promote the expression of anti‐inflammatory cytokines.^{[ 99} , ^{100 ]}

Beyond these well‐established drug classes, other small molecules have been explored as immunomodulators for IBD treatment. These include thiopurines, which inhibit T cell proliferation and activation; methotrexate, which inhibits DNA synthesis and downregulates proinflammatory cytokines; and calcineurin inhibitors and Janus kinase inhibitors.^{[ 101} , ¹⁰² , ¹⁰³ , ^{104 ]} Given the critical roles of tumor necrosis factor‐alpha (TNF‐α), interleukin‐12 (IL‐12), and IL‐23 in IBD pathogenesis, antibodies targeting these cytokines have proven to be effective therapies.^{[ 105} , ^{106 ]} Examples include infliximab, an anti‐TNF‐α monoclonal antibody, and ustekinumab, which neutralizes both IL‐12 and IL‐23 by binding to their shared p40 subunit.^{[ 107} , ^{108 ]} Additionally, integrins such as α4β7 and αEβ7 interact with cell adhesion molecules to facilitate leukocyte homing to the intestinal tract, exacerbating inflammation in IBD.^{[ 109 ]} Consequently, anti‐integrin antibodies like etrolizumab, which targets β7, have been developed for the treatment of IBD.^{[ 110 ]}

Despite these advancements, the effectiveness of IBD therapies is often hindered by inefficient delivery to disease sites.^{[ 111 ]} Orally administered drugs must overcome several physiological barriers, including the acidic pH of the stomach, digestive enzymes, and interactions with gut microbiota, to reach the primary disease sites in the colon and intestine.^{[ 112 ]} Furthermore, effective treatment requires drugs to penetrate the mucus barrier and bypass the P‐glycoprotein efflux pump to reach target cells and exert therapeutic effects.^{[ 113 ]} Nanoparticles enhance drug delivery by providing customizable functionalities to overcome these challenges, and many formulations have recently been developed.^{[ 114} , ¹¹⁵ , ^{116 ]}

The acidic environment of the stomach is a major barrier to oral drug delivery for IBD, as it can inactivate and degrade drugs before they reach the intestine and colon.^{[ 117 ]} To overcome this challenge, pH‐responsive nanomaterials have been utilized.^{[ 118 ]} For example, a cerium dioxide nanoenzyme was coated with the polyacrylic acid resin Eudragit S100, which provided protection during stomach transit in an IBD mouse model and enabled targeted release at inflamed intestinal sites.^{[ 119 ]} At these sites, the nanoenzyme neutralized hydroxyl radicals, alleviating IBD symptoms.

Elevated ROS levels are closely associated with IBD pathogenesis, making ROS‐responsive nanoparticles a promising strategy for targeted drug delivery.^{[ 120 ]} In one study, teduglutide, a glucagon‐like peptide‐2 analog that promotes intestinal repair and maintains gut barrier function, was encapsulated in nanoparticles composed of PLGA conjugated with PEG via a ROS‐sensitive thioketal linker.^{[ 121 ]} Upon oral administration, the hydrophilic and non‐ionic PEG coating reduced particle adhesion to mucin fibers, enhancing mucus penetration. In the elevated ROS environment at the disease site, the thioketal linker degraded, releasing PEG and allowing the nanoparticles to better interact with cells and deliver the teduglutide payload.

Given the harsh environment of the gastrointestinal tract and the goal of regulating inflammation in the intestinal and colonic lumen while delivering drugs intracellularly, hydrogel‐nanoparticle hybrids have been developed.^{[ 122 ]} In these systems, the hydrogel protects nanoparticles from degradation, prolongs retention, and helps regulate the microbiota in the gastrointestinal tract. For instance, PEG polymers modified with catechol as the end group were coated onto a hydrophobic core to form nanoparticles.^{[ 123 ]} These nanoparticles interacted through catechol‐mediated hydrogen bonding, forming a bioadhesive and digestive enzyme‐resistant coacervate structure. After loading dexamethasone as a model drug, this structure was orally administered, extending gastrointestinal tract retention and enabling sustained drug release. Chitosan/alginate‐based hydrogels have also been utilized to encapsulate nanoparticles for oral delivery.^{[ 124 ]} For example, resveratrol‐loaded silk fibroin nanoparticles were embedded in a chitosan/alginate hydrogel, providing protection during oral administration and enabling sustained release at inflamed colon sites, where resveratrol reduced ROS levels and alleviated inflammation in a mouse model of ulcerative colitis.^{[ 125 ]}

Inflamed sites can be passively targeted by negatively charged nanoparticles via electrostatic interactions due to the destruction of the mucus layer and overexpression of positively charged proteins such as eosinophil cationic protein and transferrin.^{[ 126 ]} For example, poly‐β‐cyclodextrin loaded with dexamethasone sodium phosphate was crosslinked with tannic acid to assemble polyphenol nanoparticles with a zeta potential of ≈−20 mV.^{[ 127 ]} These nanoparticles demonstrated enhanced targeting of inflamed colonic tissue in vivo, alleviating symptoms in a mouse model of colitis. In another study, mesoporous polydopamine nanoparticles loaded with a carbon monoxide prodrug (Fe₃(CO)₁₂) were coated with chitosan and alginate using a layer‐by‐layer strategy.^{[ 128 ]} This coating protected the nanoparticles from the acidic environment and imparted a negative surface charge, enhancing targeted accumulation at inflamed sites. There, the nanoparticles scavenged ROS while releasing carbon monoxide gas, thereby promoting M2 macrophage polarization, reducing inflammation, and ultimately restoring the intestinal barrier.

Inflamed IBD sites are also characterized by elevated expression of proteins such as CD44, CD98, and the mannose receptor.^{[ 129 ]} Consequently, active targeting nanoparticles designed to bind these proteins have been explored and can be broadly categorized into ligand‐ or antibody‐based targeting systems. For ligand‐based targeting, hyaluronic acid, which binds to CD44, has been extensively studied.^{[ 130 ]} In one study, hyaluronic acid conjugated with stearic acid via an ROS‐responsive thioketal linker formed amphiphilic micelles.^{[ 131 ]} These micelles, loaded with the STING inhibitor RU.521, accumulated in the colon and alleviated colitis in mice following oral administration. Heparin, another naturally occurring polysaccharide, can target integrins α4 and αM.^{[ 132 ]} For example, a three‐layer nanoparticle formulation was developed, where oxidation‐sensitive ε‐polylysine nanoparticles were coated with positively charged chitosan and negatively charged low‐molecular‐weight heparin.^{[ 133 ]} This coating enhanced colon accumulation in a colitis mouse model compared to uncoated nanoparticles. Pretreatment with an anti‐integrin αM antibody strongly inhibited nanoparticle uptake in activated M1 RAW264.7 macrophages, underscoring the role of heparin‐mediated targeting. Antibody‐based targeting has also been explored. For example, single‐chain anti‐CD98 antibodies were conjugated to PEG‐urocanic acid‐chitosan and then combined with polyethylenimine (PEI) and CD98 siRNA to form nanoparticles.^{[ 134 ]} Embedded in a chitosan/alginate hydrogel, these nanoparticles effectively reduced CD98 expression in an acute colitis mouse model. Compared to non‐functionalized nanoparticles, the antibody‐modified nanoparticles demonstrated enhanced cellular uptake in both Colon‐26 and RAW264.7 cells.

Aiming to leverage their unique properties, such as excellent biocompatibility, biodegradability, and inflammation‐targeting ability, cell‐derived nanoparticles, including extracellular vesicles and cell membrane‐coated nanoparticles, have been developed as promising platforms for IBD therapy.^{[ 135 ]} Among various sources, plant‐derived vesicles have been utilized to alleviate inflammation in colitis mouse models.^{[ 136} , ^{137 ]} However, their efficacy is often limited by degradation in the upper GI tract due to acidic pH and digestive enzymes. To address this challenge, enteric coatings have been explored to enhance the stability of plant‐derived vesicles. For instance, cabbage‐derived vesicles were coated with Eudragit S100, lyophilized, and encapsulated into capsules, which, upon oral administration, exhibited increased colon accumulation and improved therapeutic efficacy against IBD.^{[ 138 ]}

In addition to plant‐based vesicles, animal‐derived vesicles have also been explored. In one example, milk exosomes were collected and loaded with TNF‐α siRNA via electroporation for oral delivery.^{[ 139 ]} Compared to exosomes derived from HEK293T cells, milk exosomes demonstrated enhanced colon‐targeting efficiency, likely due to their distinct lipid composition, which primarily consists of triglycerides, phosphatidylethanolamine, diacylglycerol, and phosphatidylcholine. Notably, their high stability in the gastrointestinal tract enabled oral administration without the need for enteric coatings or hydrogel embedding, resulting in reduced TNF‐α expression levels in both the serum and colitis‐affected colon tissues. In another example, HEK293T cells were transfected with plasmids encoding IL‐10 to produce IL‐10‐loaded extracellular vesicles, which were subsequently conjugated with the ligand galactose via lipid insertion for active targeting of inflammatory macrophages overexpressing galactose‐type lectins.^{[ 140 ]} These vesicles, embedded in a chitosan/alginate hydrogel and administered orally, effectively reduced proinflammatory cytokine levels in the inflamed colon.

Cell membrane‐coated nanoparticles have also been extensively explored for biomedical applications, including drug delivery, detoxification, and vaccination.^{[ 141} , ¹⁴² , ^{143 ]} Inspired by the ability of macrophages to bind proinflammatory cytokines, macrophage membranes were derived and coated onto PLGA nanoparticles. These nanoparticles were lyophilized, loaded into gelatin capsules, and coated with enteric Eudragit S100 (Figure 6 ).^{[ 144 ]} Following oral administration, this formulation neutralized proinflammatory cytokines such as IL‐6, TNF‐α, and IL‐1β, thereby reducing inflammation both prophylactically and therapeutically in colitis mouse models. Furthermore, when macrophage‐coated PLGA nanoparticles were conjugated to green microalgae, encapsulated in capsules, and coated with Eudragit S100, the motility of the microalgae enhanced colon retention, resulting in potent efficacy in colitis mouse models.^{[ 145 ]}

Figure 6.

Macrophage cell membrane‐coated nanosponges for the treatment of IBD. A) Macrophage cell membrane‐coated nanoparticles are loaded inside a gelatin/Eudragit S‐100 capsule (cp‐MΦ‐MP) for oral delivery. B) cp‐MΦ‐MP demonstrates considerable alleviation of disease symptoms in a murine model of colitis. Adapted with permission.^{[ 144 ]} Copyright 2023, American Chemical Society.

4.2.2. Colorectal Cancer

Colorectal cancer accounts for ≈10% of newly diagnosed cancer cases and a similar percentage of cancer‐related deaths worldwide each year.^{[ 146 ]} Various treatments have been developed for colorectal cancer, including endoscopic procedures, surgery, radiotherapy, chemotherapy, targeted therapies, and immunotherapy.^{[ 147 ]} However, systemically administered drugs often exhibit low efficiency in reaching the colorectal cancer disease site, while orally administered drugs are susceptible to degradation or inactivation in the challenging gastrointestinal environment. This underscores the urgent need to develop drug delivery systems suitable for oral administration that can enhance drug accumulation at the disease site.^{[ 148 ]} Like IBD, various nanoparticulate formulations have been developed for localized applications in the gastrointestinal tract. The key strategies behind these developments include protecting drugs from the harsh gastric environment, enabling synergistic therapy via multiple drug delivery, targeting the disease site, and ensuring responsive release for enhanced accumulation. Often, multiple strategies are integrated into a single design to achieve improved therapeutic outcomes.

Two hydrophobic drugs, curcumin and SN38, were separately conjugated onto hydrophilic low molecular weight chitosan, resulting in amphiphilic polymers capable of self‐assembling into nanoparticles.^{[ 149 ]} Due to the ability of low molecular weight chitosan to reversibly open tight junctions, curcumin‐loaded nanoparticles demonstrated significantly enhanced efficacy in alleviating early‐stage colitis in colitis‐associated colorectal cancer. Additionally, the co‐delivery of curcumin and SN38 in nanoparticle form exhibited a strong synergistic effect in treating colitis‐associated colorectal cancer compared to the free drugs alone. In another study, BNS‐22, a hydrophobic DNA topoisomerase II inhibitor, was encapsulated within self‐assembling silica‐containing redox nanoparticles composed of a hydrophilic PEG segment and a hydrophobic segment containing silica and ROS‐scavenging components.^{[ 150 ]} Compared to free BNS‐22, this nanoparticle formulation improved drug accumulation in the intestine and colon, effectively inhibiting tumor growth in a colitis‐associated colorectal cancer mouse model.

To achieve chemo/magnetothermal combination therapy, the cytotoxic agent doxorubicin and superparamagnetic iron oxide nanoparticles, which generate heat under a high‐frequency magnetic field, were encapsulated within solid lipid nanoparticles.^{[ 151 ]} These nanoparticles were coated layer‐by‐layer with lipid‐linked folic acid and dextran. Following oral administration, the dextran coating was degraded by dextranase secreted primarily by colonic bacteria, exposing the folic acid for active targeting of cancer cells overexpressing folate receptors. Ex vivo imaging and doxorubicin quantification confirmed increased drug accumulation at the colon cancer site. When combined with magnetic field‐induced hyperthermia, this formulation significantly inhibited tumor growth in a CT26 orthotopic colon cancer mouse model. In a different study, a sequential targeting strategy was employed where paclitaxel was loaded into polylactic acid‐PEI nanoparticles coated with a hyaluronic acid‐inulin copolymer (Figure 7 ).^{[ 152 ]} Inulin served as a colon‐targeting carrier due to its resistance to the acidic and digestive environment in the upper gastrointestinal tract and its degradation by inulinase in the colon. Hyaluronic acid further targeted CD44‐overexpressing cancer cells. This nanoparticulate formulation significantly increased drug accumulation at the cancer site and inhibited tumor growth in a CT26 orthotopic colon cancer model. Cancer stem cells in colorectal cancer are known to contribute to recurrence and metastasis, making stemness reversal a promising treatment strategy.^{[ 153 ]} In one study, PTC209, a B cell‐specific Moloney murine leukemia virus integration site 1 inhibitor that reverses cancer cell stemness, was encapsulated into PEG‐PLGA nanoparticles with hyaluronic acid surface modifications.^{[ 154 ]} Following oral administration, these nanoparticles exhibited enhanced accumulation at the colon cancer site, inhibited primary tumor growth, and reduced intestinal tumor metastasis.

Figure 7.

Inulin‐modified nanoparticles for oral colon cancer treatment. A) PLA‐PEI and PTX self‐assemble and are subsequently complexed with hyaluronic acid‐inulin (HA‐IN) to form PTX/PPHI nanoparticles. B) The nanoparticles exhibit efficient mucopenetration ex vivo in a ligated intestinal loop model. C) The nanoparticles demonstrate strong efficacy against an orthotopic CT26‐Luc tumor model. Adapted with permission.^{[ 152 ]} Copyright 2022, Elsevier.

The oral delivery of CRISPR‐Cas9 payloads has been explored to treat colorectal cancer.^{[ 155 ]} One group utilized a poly(β‐aminoester)‐plasmid nanocomplex coated with hyaluronic acid conjugated to trimethylamine oxide. This protected the payload from the harsh environment of the digestive tract and enabled rapid mucus penetration followed by transcytosis. Using this platform, the researchers targeted the knockdown of TRAP1, a protein overly expressed in colorectal cancer that blocks inflammatory signals and promotes chemoresistance. It was found that tumor‐bearing mice treated with the nanocomplex along with fluorouracil and anti‐PD‐1 experienced inhibited tumor progression and improved survival without weight loss, representing a significant improvement compared with mice receiving monotherapies.

5. Conclusion and Outlook

Preclinical advancements in nanoparticle design for oral delivery have propelled the field forward by deepening our understanding of the biological barriers involved. Careful consideration of the administration route has led researchers to adapt well‐established nanomedicine strategies for oral delivery. Through optimization of nanoparticle properties—such as charge, size, and surface functionalization—researchers have enhanced their ability to withstand stomach acid, traverse the mucosal layer, and cross the polarized epithelial barrier without compromising payload capacity. Additionally, biomimetic approaches inspired by viruses, which naturally penetrate mucus, have further improved oral delivery outcomes.

Despite these advancements, further progress is needed for full clinical translation. A key challenge remains developing nanocarriers that achieve both mucoadhesion and mucopenetration, necessitating innovative strategies such as incorporating mucolytic enzymes to enhance therapeutic efficacy. Additionally, a deeper understanding of the biological mechanisms governing oral barriers, particularly gut epithelial cell polarization, could inform more effective nanoparticle designs for transcytosis. Another point of emphasis in the future should be the quantitative assessment of the impact of nanodelivery on oral bioavailability, which would enable a better cross‐comparison between different nanomedicine designs. Investigating the role of commensal bacteria in nanomedicine is also crucial, as their interactions within the gastrointestinal tract may significantly impact oral drug delivery. Exploring how these microorganisms coexist and influence nanoparticle behavior could inspire future delivery strategies that mimic or cooperate with them.

Given the immense potential of oral nanomedicine to benefit patients afflicted by site‐specific diseases like IBD and daily occurrence conditions like diabetes, this field remains a critical focus for research groups around the world. Successful implementation in these areas could also lead to expansion into other areas such as pain management, wound healing, and neurological diseases. Recent advancements in artificial intelligence and machine learning are anticipated to have a significant impact on the development of nanomedicines for oral delivery. Thoughtful application of this technology, paired with large, accurate data sets, could substantially increase the rate of innovation. Achieving clinical breakthroughs in this area would represent a major milestone in medicine, particularly for therapies that optimize both efficacy and patient compliance.

Conflict of Interest

The authors declare no conflict of interest.

Biographies

Luke J. Kubiatowicz is a graduate student researcher in the Aiiso Yufeng Li Family Department of Chemical and Nano Engineering at the University of California, San Diego. His research concentrates on driving biomimetic nanoparticle innovation for next‐generation nucleic acid nanomedicines.

Nima N. Pourafzal is an undergraduate student researcher in the Aiiso Yufeng Li Family Department of Chemical and Nano Engineering at the University of California, San Diego. His research focuses on the development of biomimetic nanoparticles to overcome biological barriers.

Audrey Ting Zhu is an undergraduate working in the Aiiso Yufeng Li Family Department of Chemical and Nano Engineering at the University of California, San Diego. Her research focuses on the utilization of biomimetic nanoparticles for vaccination.

Zhongyuan Guo is a graduate student researcher in the Aiiso Yufeng Li Family Department of Chemical and Nano Engineering at the University of California, San Diego. His research focuses on the development of biomimetic nanoparticles for targeted drug delivery and vaccine applications, with an emphasis on treating cancer, infectious diseases, and inflammatory disorders.

Ronnie H. Fang is an Assistant Professor in the Department of Pediatrics at the University of California, San Diego. He received his Ph.D. in NanoEngineering at the University of California, San Diego. His research is focused on leveraging biomimetic nanoparticles for drug delivery and immunoengineering applications.

Liangfang Zhang is the Joan and Irwin Jacobs Chancellor Professor in the Aiiso Yufeng Li Family Department of Chemical and Nano Engineering at the University of California, San Diego. He received his Ph.D. in Chemical and Biomolecular Engineering at the University of Illinois at Urbana‐Champaign. His research focuses on creating innovative biomimetic nanotechnologies for biomedical applications such as countermeasures, drug delivery, and vaccines.

Kubiatowicz L. J., Pourafzal N., Zhu A. T., Guo Z., Fang R. H., and Zhang L., “Nanomedicine for Oral Delivery: Strategies to Overcome the Biological Barriers.” Small Methods 10, no. 2 (2026): 2500624. 10.1002/smtd.202500624