Acute kidney injury (AKI) involves oxidative stress, inflammation, and metabolic toxin accumulation, leading to renal dysfunction and systemic metabolic disorders. Current treatments provide limited efficacy and fail to address the interplay between renal and intestinal pathologies. Here, we present a noninvasive dual-action oral platform that integrates systemic and gut-targeted therapeutic effects to restore homeostasis along the gut-kidney axis. The system employs a choline-quercetin ionic liquid (ChQ-IL) as the active pharmaceutical ingredient, encapsulated within pH-responsive, calcium-crosslinked alginate microparticles (Alg MPs). These MPs are fabricated using an interfacial microfluidic solidification technique developed in this study to ensure uniformity and scalability. ChQ-IL markedly enhances quercetin solubility and intestinal permeability while preserving its antioxidant and anti-inflammatory activities, whereas Alg MPs provide gastric protection, controlled intestinal release, and prebiotic-like benefits. In a glycerin-induced AKI mouse model, oral administration of ChQ-IL@Alg MPs significantly alleviates oxidative stress, inflammation, renal injury, and uremic toxin accumulation through systemic delivery, while concurrently enhancing short-chain fatty acid production, restoring gut metabolic balance, and preventing body weight loss via gut-targeted effects. This dual-action modulation of the gut-kidney axis establishes ChQ-IL@Alg MPs as a scalable, safe, and patient-compliant oral platform that offers integrated renal and metabolic protection for next-generation AKI therapy.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is closely associated with autonomic imbalance and inflammation. While low-level vagus nerve stimulation (LL-VNS) offers therapeutic benefits, its clinical application is limited by the need for surgical implants. Here, we present a noninvasive, orally delivered magnetoelectric neuroimmunomodulation platform that targets the gut-brain-spleen-heart axis to deliver LL-VNS for AF therapy. The platform comprises ingestible microparticles (MPs) embedding magnetostrictive Fe3O4@BaTiO3 nanogenerators (FO@BTO NGs) within a conductive matrix of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), which facilitates electrical signal transmission, and dopamine-alginate, which promotes gastric adhesion via catechol-mediated interactions. After oral gavage in a rat AF model, MPs adhere to the stomach lining and, upon alternating magnetic activation, FO@BTO NGs generate pulsed electrical currents that stimulate vagal afferent fibers. This activates brainstem autonomic circuits, enhancing parasympathetic tone and suppressing sympathetic activity. Concurrently, it engages the splenic neuroimmune circuit via the cholinergic anti-inflammatory pathway, thereby reducing systemic inflammation. This dual neuroimmune modulation significantly shortens AF duration and mitigates cardiac inflammation and electrical remodeling. These findings establish a clinically translatable, implant-free strategy for delivering LL-VNS through coordinated neural and immune pathways, offering a safe and accessible alternative to implantable systems for AF management.

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the inflamed substantia nigra, resulting in striatal dopamine (DA) depletion and severe motor dysfunction. Here, we report a chemically programmed, inflammation-responsive prodrug nanoparticle (NP) system-β-glucans-DA(OAc)2 NPs-that enables precise oral gut-to-brain delivery of DA into deep brain regions. In this design, the acetylated DA prodrug DA(OAc)2 is conjugated to β-glucans via a reactive oxygen species (ROS)-cleavable thioketal linker, thereby preventing DA autooxidation, enhancing stability during transit, and ensuring selective activation at neuroinflammatory sites. Following oral administration in PD mice, the NPs are recognized by Dectin-1, internalized by intestinal macrophages, and trafficked through the lymphatic and systemic circulation to cross the blood-brain barrier, ultimately homing specifically to the inflamed substantia nigra in the deep brain. Within this pathological niche, dual responsiveness to elevated ROS and enzymatic activity triggers controlled prodrug cleavage, sustained DA regeneration, and restoration of striatal DA via the nigrostriatal pathway, ultimately rescuing motor function. This inflammation-guided, modular prodrug platform provides a noninvasive and precise strategy for dopaminergic therapy, underscoring its potential as a transformative approach for PD management.

Macrophages (MΦ) in the tumor microenvironment (TME) are often skewed toward the M2 phenotype, which suppresses immune responses and supports tumor progression. Interferon-γ (IFN-γ) plays a pivotal role in reprogramming MΦ toward a pro-inflammatory M1-like phenotype, thereby enhancing anti-tumor immunity. This study introduces a targeted oral immunotherapy strategy using IFN-γ mRNA-loaded lipid nanoparticles conjugated with β-glucans (IFN-γ mRNA@βGlus-LNPs), evaluated in a mouse model of triple-negative breast cancer. Following oral administration, the nanoparticles target transcytotic M cells in Peyer's patches, are taken up by endogenous MΦ in intestinal lymphoid tissues, and transported via lymphatic and systemic circulation to the tumor site. In the TME, the nanoparticles induce transient, localized IFN-γ expression, reprogramming both infiltrating and resident MΦ toward an M1-like phenotype and activating cytotoxic T cell responses. By harnessing the natural tumor-homing ability and biocompatibility of MΦ, this "Trojan horse" approach offers a promising platform for effective, safe mRNA-based cancer immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis and a high propensity for liver metastasis. This study presents an innate immunity-guided, macrophage (MΦ)-homing nanoplatform that enables oral delivery of theranostic agents to PDAC lesions by harnessing the migratory behavior of endogenous MΦ toward tumor-derived immune cues. The nanoplatform integrates a βGlus-R848 prodrug-constructed by conjugating β-glucans (βGlus) with the immunomodulator resiquimod (R848) via a reactive oxygen species (ROS)-responsive thioketal linker-and Ag2Te quantum dots (QDs) for near-infrared II (NIR-II) imaging, forming βGlus-R848/Ag2Te nanoparticles (NPs). Upon oral administration, βGlus facilitates the selective uptake of NPs by intestinal MΦ (βGlus-R848/Ag2Te NPs@MΦ), which subsequently migrate to the tumor microenvironment (TME). There, elevated ROS levels trigger the release of R848, reprogramming tumor-associated MΦ from an immunosuppressive M2 to an immunoactive M1 phenotype. This immune activation remodels the stroma, enhances T cell infiltration, and transforms the TME into an immunoactive state, thereby improving therapeutic outcomes. Concurrently, Ag2Te QDs enable deep-tissue NIR-II imaging for real-time visualization of PDAC progression, liver metastasis, and treatment response. Guided by innate immune signals, this MΦ-homing theranostic platform offers a promising strategy to overcome current challenges in PDAC treatment by integrating targeted immunotherapy with noninvasive, real-time disease monitoring.

Sepsis presents a significant medical challenge due to its intense inflammatory response to infection, often resulting in high mortality rates. A promising therapeutic strategy targets the cholinergic anti-inflammatory pathway (CAIP), which regulates immune responses. This study investigates the ingestion of piezoelectric particles that adhere to the stomach lining, specifically targeting TRPV1 receptors. In a mouse model of sepsis, these particles, when activated by low-intensity pulsed ultrasound, generate mild electrical pulses. These pulses stimulate vagal afferent fibers, transmitting signals to the brain and modulating the neural-immune network via the CAIP. Consequently, this leads to a reduction in systemic inflammation, mitigating weight loss, alleviating multiple tissue injuries, and preventing death by modulating immune cells in the spleen. This approach addresses the critical need for noninvasive sepsis therapies, potentially improving patient outcomes. Utilizing portable ultrasound equipment with minimal thermal effects, this technique offers a safe and convenient treatment option, even for home use.

Molecular hydrogen (H2) has emerged as a promising therapeutic agent owing to its selective antioxidant and anti-inflammatory properties, as well as its ability to modulate cellular signaling, metabolism, and immune responses. Beyond mitigating oxidative stress and inflammation, H2 shows anticancer potential by altering the tumor microenvironment and inducing apoptosis. Despite encouraging findings from preclinical and clinical studies, conventional delivery routes—such as inhalation, oral intake of H2-rich water, or injection of H2-rich saline—face critical limitations in stability, bioavailability, and targeted delivery, impeding clinical translation. This review first outlines the therapeutic mechanisms of H2, including redox regulation, inflammatory modulation, and tumor suppression. It then discusses current delivery approaches, their therapeutic outcomes, and inherent challenges. To overcome these barriers, a variety of advanced H2-delivering systems have been developed, including H2-containing carriers and in situ H2-generating materials based on water-, acid-, and electrochemical reactions. Externally stimulated platforms, such as photo-, sono-, and electro-catalysis-based systems, enable spatiotemporally controlled H2 release in response to disease-specific cues. Additionally, microbiota-targeted approaches involving probiotics and prebiotics offer indirect yet sustained H2 delivery via gut fermentation. The review concludes by addressing key challenges—such as material scalability, biosafety, and integration with existing therapies—and highlights future directions for optimizing H2 delivery through interdisciplinary innovation in materials science and medicine.

Conductive biomaterials have shown promising results for correcting pathological cardiac electrical signaling. However, their mechanisms of operation are still largely unclear. One reason behind disrupted cardiac intercellular communication, though, is lowered expression of the gap junction protein connexin43 (Cx43), which may be alleviated by conductive biomaterials. In this study, we aimed to test this hypothesis, using the self-doping conductive biomaterial poly-3-amino-4-methoxybenzoic acid-gelatin (PAMB-G). An in vitro model was established, in which cardiomyocytes (CMs) were treated with anisomycin, while the in vivo model involved anisomycin-treated mice subjected to electrical pacing to induce atrial fibrillation (AF). Cx43 expression, Ca2+ transient propagation, and CM electrical conduction in vitro, as well as the in vivo effects of PAMB-G on AF, were evaluated; additionally, the underlying molecular mechanisms were identified. We found that anisomycin, at different concentrations, down-regulated Cx43; this was counteracted by PAMB-G, which restored proper Cx43 expression, coupled with improved Ca2+ signal and electrical conduction. Cx43 restoration was due to PAMB-G suppressing anisomycin-induced activation of MAPKs P38 and JNK, which are involved in phosphorylating Cx43 for degradation. Similar observations were also found in vivo, where a PAMB-G patch acted against anisomycin-induced Cx43 downregulation and impaired atrial cell communication, subsequently alleviating pacing-induced AF. Therefore, PAMB-G suppresses MAPKs, in turn upregulating Cx43, leading to improved electrical signal transduction. As a result, modulating the MAPK-Cx43 pathway, such as with PAMB-G, could serve as a potential therapeutic strategy for cardiac arrhythmia. STATEMENT OF SIGNIFICANCE: Disruption of atrial intercellular gap junction channels, comprised of connexins, leads to atrial fibrillation (AF), the most prevalent arrhythmia, with poor clinical outcomes. Current AF treatments are associated with adverse effects, and only focus on managing symptoms, thereby necessitating innovative treatment strategies. One such strategy is conductive biomaterials, which show promising results for correcting pathological cardiac electrical signaling. We synthesized a self-doping conductive biomaterial, poly-3-amino-4-methoxybenzoic acid-gelatin (PAMB-G), and found that it counteracts against anisomycin-induced connexin43 (Cx43) downregulation, subsequently improving cardiac electrical conduction and alleviating pacing-induced AF. This is owed to PAMB-G suppressing anisomycin-associated activation of mitogen-activated kinases P38 and JNK, which are involved in phosphorylating Cx43 for degradation. Therefore, PAMB-G modulation of MAPK-Cx43 pathway could aid in cardiac arrhythmia treatment.

Electrical and structural remodeling disrupt atrial electrical conduction, leading to atrial fibrillation (AF). Epicardially delivered conductive biomaterial patches can effectively transmit electrical signals and potentially diminish AF. However, given the progressive nature of AF development, continuous and noninvasive monitoring is essential for assessing the therapeutic efficacy of these patches over time. In this study, superparamagnetic iron oxide nanoparticles (SPIO NPs) are synthesized and used to label a bio-conductive patch made of poly-3-amino-4-methoxybenzoic acid (PAMB) conjugated to gelatin (PAMBG-NP). Incorporating SPIO NPs does not alter the mechanical, electrical, or biocompatible properties of PAMBG. PAMBG-NP restores conduction velocity, suppresses rotor generation, and prevents re-entry currents, thereby relieving AF burden in an in vitro pacing model. In vivo, a bell-shaped PAMBG-NP patch is applied to the right and left atria of KCNE1 knockout mice. Compared to its Gelatin-NP counterpart, PAMBG-NP significantly reduces AF duration and enhances post-AF recovery over a 60-day period. Furthermore, magnetic resonance imaging indicates that PAMBG-NP degrades more slowly than Gelatin-NP, along with having a reduced incidence of AF in PAMBG-NP-treated animals. Therefore, incorporating SPIO NPs into PAMBG enables real-time, in vivo monitoring, potentially facilitating the noninvasive evaluation of its therapeutic efficacy.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer. Paclitaxel (PTX), typically administered intravenously (IV) as chemotherapy, shows promise for triggering immunogenic cell death (ICD) and may serve as a potential immunotherapy. This study introduces an oral PTX delivery method using an enteric-coated gelatin capsule containing capric acid oil and an effervescent agent, optionally with decylamine-conjugated β-glucans (DA-βGlus). Upon dissolving in the small intestine, the capsule undergoes an effervescence reaction that produces emulsified oil droplets (ODs) by bile salts, forming either Bared/ODs/PTX or DA-βGlus/ODs/PTX, with the latter featuring surface-attached DA-βGlus. The study evaluates the oral absorption, pharmacokinetics, and therapeutic efficacy of these formulations, comparing them to IV administration. IV PTX causes rapid spikes in plasma concentration, quick metabolism, and elimination, which can be unsafe. In contrast, the oral delivery system maintains consistent drug levels in the bloodstream for longer periods, improving overall effectiveness. Bared/ODs/PTX follows conventional fat absorption pathways, limiting tumor targeting. On the other hand, DA-βGlus/ODs/PTX uses DA-βGlus to enhance specificity for tumors through endogenous macrophage-mediated transport, effectively acting as “cellular tumor-seeking vehicles”. This method reduces tumor stroma fibrosis, delivers PTX precisely, induces apoptosis, triggers PTX-induced ICD, and enhances cytotoxic T cell responses, augmenting targeted anti-PDAC strategies.

Addressing the critical requirement for real-time monitoring of tumor progression in cancer care, this study introduces an innovative wearable platform. This platform employs a thermoplastic polyurethane (TPU) film embedded with hafnium oxide nanoparticles (HfO2 NPs) to facilitate dynamic tracking of tumor growth and regression in real time. Significantly, the synthesized HfO2 NPs exhibit promising characteristics as effective sonosensitizers, holding the potential to efficiently eliminate cancer cells through ultrasound irradiation. The TPU-HfO2 film, acting as a dielectric elastomer (DE) strain sensor, undergoes proportional deformation in response to changes in the tumor volume, thereby influencing its electrical impedance. This distinctive behavior empowers the DE strain sensor to continuously and accurately monitor alterations in tumor volume, determining the optimal timing for initiating HfO2 NP treatment, optimizing dosages, and assessing treatment effectiveness. Seamless integration with a wireless system allows instant transmission of detected electrical impedances to a smartphone for real-time data processing and visualization, enabling immediate patient monitoring and timely intervention by remote medical staff. By combining the dynamic tumor monitoring capabilities of the TPU-HfO2 film with the sonosensitizer potential of HfO2 NPs, this approach propels cancer care into the realm of telemedicine, representing a significant advancement in patient treatment.

Obesity is a significant health concern that often leads to metabolic dysfunction and chronic diseases. This study introduces a novel approach to combat obesity using orally ingested self-powered electrostimulators. These electrostimulators consist of piezoelectric BaTiO3 (BTO) particles conjugated with capsaicin (Cap) and aim to activate the vagus nerve. Upon ingestion by diet-induced obese (DIO) mice, the BTO@Cap particles specifically target and bind to Cap-sensitive sensory nerve endings in the gastric mucosa. In response to stomach peristalsis, these particles generate electrical signals. The signals travel via the gut-brain axis, ultimately influencing the hypothalamus. By enhancing satiety signals in the brain, this neuromodulatory intervention reduces food intake, promotes energy metabolism, and demonstrates minimal toxicity. Over a 3-week period of daily treatments, DIO mice treated with BTO@Cap particles show a significant reduction in body weight compared to control mice, while maintaining their general locomotor activity. Furthermore, this BTO@Cap particle-based treatment mitigates various metabolic alterations associated with obesity. Importantly, this noninvasive and easy-to-administer intervention holds potential for addressing other intracerebral neurological diseases.

mRNA vaccines for cancer immunotherapy are commonly delivered using lipid nanoparticles (LNPs), which, when administered intravenously, may accumulate in the liver, potentially limiting their therapeutic efficacy. To overcome this challenge, the study introduces an oral mRNA vaccine formulation tailored for efficient uptake by immune cells in the gastrointestinal (GI) tract, known for its high concentration of immune cells, including dendritic cells (DCs). This formulation comprises mRNA complexed with β-glucans (βGlus), a potential adjuvant for vaccines, encapsulated within LNPs (βGlus/mRNA@LNPs). The βGlus/mRNA complexes within the small compartments of LNPs demonstrate a distinctive ability to partially dissociate and reassociate, responding to pH changes, effectively shielding mRNA from degradation in the harsh GI environment. Upon oral administration to tumor-bearing mice, βGlus/mRNA@LNPs are effectively taken up by intestinal DCs and local nonimmune cells, bypassing potential liver accumulation. This initiates antigen-specific immune responses through successful mRNA translation, followed by drainage into the mesenteric lymph nodes to stimulate T cells and trigger specific adaptive immune responses, ultimately enhancing antitumor effects. Importantly, the vaccine demonstrates safety, with no significant inflammatory reactions observed. In conclusion, the potential of oral βGlus/mRNA@LNPs delivery presents a promising avenue in cancer immunotherapy, offering needle-free and user-friendly administration for widespread adoption and self-administration.

Significant health risks are posed by meningitis due to its rapid progression, and challenges are encountered in intravenous antibiotic administration, especially in crossing the blood-brain barrier. To address this, an inflammation-activated, endogenous macrophage (M Phi)-mediated oral prodrug delivery system is developed for targeted therapeutic interventions in bacterial meningitis treatment. This system is guided by inflammation-derived chemoattractants and triggers drug release through inflammation-induced reactive oxygen species (ROS). Comprised of naturally derived beta-glucans conjugated with the antibiotic cefotaxime (CTX) using a ROS-responsive linker, nanoparticles (beta Glus-CTX NPs) are formed in aqueous solutions. In a mouse model of Klebsiella pneumoniae-induced meningitis, orally administered beta Glus-CTX NPs are traversed by intestinal microfold cells, surpassing the intestine-epithelial barrier, and are absorbed by resident endogenous M Phi. These M Phi-mediated drug delivery vehicles are then traveled through the lymphatic and circulatory systems, crossing the compromised blood-brain barrier, ultimately reaching inflamed brain tissues, guided by their derived chemoattractants. In ROS-rich inflamed tissue environments, the linkers in the beta Glus-CTX NPs are cleaved, releasing therapeutic CTX for localized treatment. Targeted antibiotic treatment for bacterial meningitis is offered by this oral, endogenous M Phi-mediated prodrug delivery system, overcoming the robust gut-to-brain biological barriers and potentially enhancing effectiveness for comfortable home-based treatment. Guided by chemoattractants released from inflamed tissues, the prodrug nanoparticles, transported by endogenous M Phi, traverse the lymphatic and circulatory systems, ultimately reaching the infected brain. This inflammation-activated M Phi-mediated delivery system not only overcomes substantial biological barriers between the gut and the brain but also responds to elevated ROS levels in inflamed tissues, triggering the release of the therapeutic drug. image

Spinal cord injury (SCI), caused by significant physical trauma, as well as other pathological conditions, results in electrical signaling disruption and loss of bodily functional control below the injury site. Conductive biomaterials have been considered a promising approach for treating SCI, owing to their ability to restore electrical connections between intact spinal cord portions across the injury site. In this study, we evaluated the ability of a conductive hydrogel, poly-3-amino-4-methoxybenzoic acid-gelatin (PAMB-G), to restore electrical signaling and improve neuronal regeneration in a rat SCI model generated using the compression clip method. Gelatin or PAMB-G was injected at the SCI site, yielding three groups: Control (saline), Gelatin, and PAMB-G. During the 8-week study, PAMB-G, compared to Control, had significantly lower proinflammatory factor expression, such as for tumor necrosis factor -α (0.388 ± 0.276 for PAMB-G vs. 1.027 ± 0.431 for Control) and monocyte chemoattractant protein (MCP)-1 (0.443 ± 0.201 for PAMB-G vs. 1.662 ± 0.912 for Control). In addition, PAMB-G had lower astrocyte and microglia numbers (35.75 ± 4.349 and 40.75 ± 7.890, respectively) compared to Control (50.75 ± 6.5 and 64.75 ± 10.72) and Gelatin (48.75 ± 4.787 and 71.75 ± 7.411). PAMB-G-treated rats also had significantly greater preservation and regeneration of remaining intact neuronal tissue (0.523 ± 0.059% mean white matter in PAMB-G vs 0.377 ± 0.044% in Control and 0.385 ± 0.051% in Gelatin) caused by reduced apoptosis and increased neuronal growth-associated gene expression. All these processes stemmed from PAMB-G facilitating increased electrical signaling conduction, leading to locomotive functional improvements, in the form of increased Basso-Beattie-Bresnahan scores and steeper angles in the slope test (76.667 ± 5.164 for PAMB-G, vs. 59.167 ± 4.916 for Control and 58.333 ± 4.082 for Gelatin), as well as reduced gastrocnemius muscle atrophy (0.345 ± 0.085 for PAMB-G, vs. 0.244 ± 0.021 for Control and 0.210 ± 0.058 for Gelatin). In conclusion, PAMB-G injection post-SCI resulted in improved electrical signaling conduction, which contributed to lowered inflammation and apoptosis, increased neuronal growth, and greater bodily functional control, suggesting its potential as a viable treatment for SCI.

Ethanol is a potential causative factor of gastric ulcers, which are associated with gastric injury and the overproduction of reactive oxygen species. Molecular hydrogen (H2) is reportedly a benign antioxidant and boric acid is an effective medication in repairing deep wounds. In this work, a nanoparticle system that consists of potassium borohydride ionic nanocrystals (KBH4 NCs) with a high H2 storage capacity is developed for the treatment and prevention of ethanol-induced gastric ulcers in mice. H2-rich water (HRW) is used as a control. Since the evolution of gaseous H2 from the HRW is abrupt, most of the evolved H2 gas is lost to the surrounding environment before and during oral administration. By contrast, KBH4 NCs can be trapped at the defect sites of ulcerated regions, reacting with the gastric fluid to generate sustainably gaseous H2 and boric acid, mitigating oxidative stress and excessive inflammation in tissues and repairing the gastric injury. Additionally, the protection that is afforded by gastric mucosa against ethanol-induced damage is stronger in mice that have been pretreated with KBH4 NCs than in those that have been pretreated with HRW, indicating the protective effect of KBH4 NCs. Overall, the data suggest that the as-developed KBH4 NCs are a promising oral formulation for the effective management of gastric ulcers.

During tissue infection, immune cells undergo glycolysis, generating lactate that intensifies inflammation and contributes to the excessive production of reactive oxygen species (ROS) and pro-inflammatory cytokines. TiO2 serves as a photocatalyst capable of splitting water and producing H2 when activated by UV light. The study proposes the clinical application of TiO2 to combat tissue inflammation, building upon the antioxidative properties of H2. To address the limited tissue penetration depth of UV light, a TiO2-based photocatalytic H2 production system is developed, utilizing upconversion nanoparticles (UCNPs) coated with a double-shell structure of SiO2 and TiO2 (UST NPs). The efficiency of the UST NPs relies on the utilization of tissue-penetrating near-infrared (NIR) light, which is converted to UV light by the UCNP core. Additionally, the SiO2@TiO2 double-shell enhances light absorbance efficiency and photocatalytic activity. When exposed to NIR light, the UST NPs have the potential to effectively enhance H2 production by utilizing lactate as a sacrificial agent in inflamed tissues, while also facilitating the photocatalytic water splitting process. Consequently, UST NPs + NIR efficiently deplete accumulated lactate in inflamed tissues, reducing inflammation by utilizing the produced H2 to scavenge ROS and pro-inflammatory cytokines. The study explores the innovative application of TiO2-based materials as a photocatalyst, providing fresh perspectives on enhancing H2 production efficiency through the utilization of UCNPs, NIR light, and glycolysis-generated waste (lactate) in inflammation, and examining its relevance in the medical field.

The prognosis in cases of pancreatic ductal adenocarcinoma (PDAC) with current treatment modalities is poor owing to the highly desmoplastic tumor microenvironment (TME). Herein, a β‐glucans‐functionalized zinc–doxorubicin nanoparticle system (βGlus‐ZnD NPs) that can be orally administered, is developed for targeted PDAC therapy. Following oral administration in PDAC‐bearing mice, βGlus‐ZnD NPs actively target/transpass microfold cells, overcome the intestinal epithelial barrier, and then undergo subsequent phagocytosis by endogenous macrophages (βGlus‐ZnD@Mϕ). As hitchhiking cellular vehicles, βGlus‐ZnD@Mϕ transits through the intestinal lymphatic system and enters systemic circulation, ultimately accumulating in the tumor tissue as a result of the tumor‐homing and “stealth” properties that are conferred by endogenous Mϕ. Meanwhile, the Mϕ that hitchhikes βGlus‐ZnD NPs is activated to produce matrix metalloproteinases, destroying the desmoplastic stromal barrier, and differentiates toward the M 1 ‐like phenotype, modulating the TME and recruiting effector T cells, ultimately inducing apoptosis of the tumor cells. The combination of βGlus‐ZnD@Mϕ and immune checkpoint blockade effectively inhibits the growth of the primary tumor and suppresses the development of metastasis. It thus represents an appealing approach to targeted PDAC therapy.

The formulation of a drug using high-energy emulsification commonly causes drug deterioration. Exploiting the well-known Diet Coke-Mentos reaction (DCMR), a U-shaped tube reactor that can generate an eruption of bubbly flow that can serve as a low-energy emulsification platform, is proposed. The liquid in the U-tube reactor is a supersaturated solution of aqueous CO2, which mimics Diet Coke. When glass beads with rough surfaces, mimicking Mentos, are dropped into the carbonated water, an eruptive bubbly flow is spontaneously created, mediating effective emulsification at a compound water-oil interface. Experimental results demonstrate that DCMR-mediated bubbly flow may provide a versatile platform for the production of "oil-in-water" or "water-inoil" droplets and Pickering emulsion composite particles as drug carriers. The DCMR-derived bubbly flow is generated without significant temperature elevation, so the activity of the drug to be emulsified is unaffected. In vivo results reveal the feasibility of using this low-energy emulsification platform to formulate an emulsion system that contains catalase, a temperature-sensitive oxidoreductase, to mitigate an experimentally formed paw inflammation in mice. The as-proposed emulsification platform is attractive for formulating numerous drug delivery systems on a small-scale in a customized manner to meet the needs of each individual for personalized medicine.