Naringenin (NAR) possesses remarkable hepatoprotective potential. However, its extremely low aqueous solubility and oral bioavailability greatly constrain its therapeutic efficacy. To overcome these limitations, we developed a novel oral nanodelivery system, NanoNAR@Glycygel, by embedding NAR nanosuspensions (NanoNAR) into a self-assembled glycyrrhizin-based hydrogel (Glycygel). The design of this delivery system improves solubility, enhances absorption, and provides synergistic hepatoprotective effects. NanoNAR, when stabilized by the natural biosurfactant glycyrrhizin, exhibited a uniform particle size of approximately 230 nm and showed markedly improved solubility in physiologically relevant media. The hydrogel network formed by Glycygel effectively encapsulated NanoNAR, further enhancing its solubility and controlled release behavior. Pharmacokinetic analyses revealed that NanoNAR@Glycygel significantly enhanced the oral bioavailability of NAR and increased its hepatic accumulation, demonstrating how the synergistic interplay between nanonization and the glycyrrhizin hydrogel matrix facilitates rapid absorption and sustained release. In a cholestatic liver injury mouse model, NanoNAR@Glycygel treatment markedly alleviated cholestasis and hepatic histopathological damage, restoring liver morphology and serum biochemical parameters to near-normal levels. Mechanistic investigations revealed for the first time that HMGB1 signaling is involved in this cholestatic liver injury, and NanoNAR@Glycygel exerted its potent therapeutic effect by inhibiting this signaling. The NanoNAR@Glycygel cloud also reduced malondialdehyde (MDA) levels and enhanced superoxide (SOD) activity, thereby mitigating oxidative injury. Collectively, these findings demonstrate that NanoNAR@Glycygel is a safe, simple, and highly effective oral delivery platform that not only unleashes the therapeutic potential of NAR but also highlights the distinctive advantages of glycyrrhizin-based matrices for the targeted oral delivery of hydrophobic natural bioactives.

Tacrolimus (FK506) has limited clinical applications due to its poor solubility and narrow therapeutic window. Therefore, strategies to enhance its solubility and enable personalized dosing are highly valuable. Recently, loading drug molecules into mesoporous silica has emerged as a novel strategy to improve the solubility of poorly soluble drugs. Concurrently, 3D printing technology offers a new approach for fabricating personalized dosage forms for drugs with a narrow therapeutic index. In this study, poly(ethylene glycol) 32-stearate was selected as the matrix material and combined with the drug-loaded solid dispersion to successfully prepare semi-solid materials with good printability under anhydrous conditions. This approach effectively addresses the challenge of maintaining the drug in an amorphous state. Using semi-solid extrusion (SSE) 3D printing technology, the material was fabricated into tablets of four different sizes. The successful loading of the drug in its amorphous form was confirmed by characterization techniques including differential scanning calorimetry (DSC), X-ray diffraction (XRD), and nitrogen adsorption analysis (BET/BJH). Physico-mechanical characterization, content uniformity testing, in vitro dissolution studies, and stability tests demonstrated that the printed tablets possess satisfactory mechanical properties, meet the requirements for in vitro dissolution, and exhibit excellent stability. This study presents a promising strategy for personalized therapy with FK506.

Emerging and re-emerging infectious diseases ranging from the 1918 H1N1 influenza pandemic to the recent SARS-CoV-2 and monkeypox virus outbreaks continue to pose profound threats to global public health. These crises underscore the critical need for high-fidelity and human-relevant infection models. Organoid technology has emerged as a cornerstone platform for pathogen research by faithfully recapitulating the 3-dimensional architecture and physiological microenvironment of native human tissues in vitro. This review systematically examines the development and structural refinement of organoid-based infection models with an emphasis on evidence-based strategies for stem cell source selection, extracellular matrix optimization, and dynamic culture system engineering. Such advancements enable the robust generation of multi-organ models including respiratory, intestinal, and neural organoids tailored for investigating viral tropism, spatiotemporal infection kinetics, and host immune responses. Furthermore, we evaluate the translational utility of organoids in high-throughput antiviral drug screening and preclinical vaccine assessment. To further enhance physiological relevance and functional fidelity, organoid platforms are being increasingly combined with advanced engineering strategies, including coculture approaches, CRISPR-Cas9-mediated genetic perturbation, engineered microphysiological systems (such as organ-on-a-chip), and 3D bioprinting. These integrated technologies improve biomimicry while expanding experimental controllability and scalability. In addition, we critically examine the major bottlenecks limiting clinical translation and discuss emerging frontiers driven by artificial intelligence and synthetic biology. Through iterative technological refinement and cross-disciplinary convergence, organoids have evolved beyond reductionist in vitro surrogates into physiologically informed and mechanism-driven platforms that advance our understanding of host-pathogen interactions while enhancing global preparedness against emerging pathogens.

3D printing technology is characterized by highly personalized, small batch production, and excellent reproducibility. These features enable it to address the limitations of traditional dose-dividing methods currently employed in medical institutions, thereby fulfilling the diverse dosing requirements of patients. In this study, we developed two individual dosing strategies for formulating 3D printing pharmaceutical formulations (3DPF) and 3D printing divided-dose tablets (3DPDT). Specifically, 3DPF were prepared using a gel ink containing propranolol hydrochloride as the active pharmaceutical ingredient, while 3DPDT were fabricated using a paste ink incorporating powdered commercial tablets. We investigated the rheological properties of the gel and paste ink, and assessed the mechanical properties, assay, and dissolution profile of tablets. The results indicate that the appearance, mechanical properties, drug content, content uniformity and drug dissolution rate of 3DPF and 3DPDT meet the United States Pharmacopoeia-National Formulary 2024 (USP-NF 2024) requirements. These strategies demonstrate highly reproducible and high-quality tablet preparation capabilities, which are applicable in drug development and pharmacy services. Furthermore, these approaches effectively resolve the issue of fixed dosages in commercially available drugs failing to meet the personalized medication needs of special populations. They provide a novel and promotable individual dosing solution tailored to the medication requirements of various patient groups.

As an emerging technology, 3D printing facilitates the fabrication of complex preparations and enables controlled drug release. This study integrated semi-solid extrusion (SSE) and fused deposition modeling (FDM) to develop core-shell structured sustained-release tablets (CSRT) with varying release profiles, exploring how structural design influences release behavior. Propranolol hydrochloride was selected as the model drug. Drug-loaded cores with different filling rates were prepared using SSE and characterized for appearance, hardness, XRD, and release properties. Shells with varying release windows were fabricated using FDM. Subsequently, shells and cores were assembled. Micro-CT was employed for microstructural characterization, while drug assay and release properties were assessed. The results indicated that cores exhibited a good appearance, and the SSE process had no effect on the crystal type. Adjusting the filling rate allowed for slight modulation of drug release while the shell structure effectively prolonged drug release. The CSRT displayed no significant internal defects, and the assay met the United States Pharmacopoeia-National Formulary 2024 (USP-NF 2024) requirements. Adjusting release windows resulted in a sustained release ranging from 8 to 24 h, with the release profile conforming to first-order kinetics (R2 values ranging from 0.961 to 0.999). These findings provide practical strategies for controlling drug release rates.

During the COVID-19 pandemic, the use of lipid nanoparticles (LNPs) augmented the development of mRNA vaccines. However, their ultralow-temperature storage and transportation requirements, as well as their heavy reliance on injection by professional medical staff, have limited large-scale vaccination in many developing countries. Herein, we developed a simple and widely deployable microneedle (MN) vaccine delivery system (mLNP-man-MN) for mannose-modified LNPs (mLNP-man) loaded with mRNA encoding the SARS-CoV-2 spike receptor-binding domain by utilizing three-dimensional printing and polydimethylsiloxane micro molding methods. This delivery system is composed of a dissolvable polymer mixture that was optimized for high bioactivity by screening formulations in vitro. We have demonstrated that this MN system can maintain the physicochemical properties and bioactivity of the mRNA-LNP complex even when stored at 4 °C for at least one month or at 25 °C for two weeks. Moreover, mLNP-man-MNs target the epidermis and dermis, which are rich in antigen-presenting cells, thereby eliciting effective innate immune responses and inducing robust systemic humoral responses, as well as multifunctional cellular immunity in the spleen. Importantly, the MN system induced a certain level of pulmonary T-cell responses compared to those induced by intramuscular injections, thereby providing some protection against lung invasion by the SARS-CoV-2 pseudovirus in mice.

Individuals with special needs, such as children, the elderly, and the visually impaired, encounter significant hurdles in the field of personalized pharmacotherapy due to their distinctive medication needs. 3D printing technology, a novel approach for preparing drug products with intricate personalized designs, has shown considerable promise in improving the safety and adherence to patient medication regimens. This study chose acetaminophen, a commonly employed antipyretic analgesic, as the model drug and employed binder jetting 3D printing (BJ-3DP) to manufacture oral disintegrating tablets (ODTs) with multiple specifications and complex structures. The study initiated with an assessment of the printable properties of powder and ink formulations, proceeding to craft ODTs with individualized dosages and surfaces embedded in QR codes, cartoon figures, textual information, and raised braille. These tablets are internally designed with spaces that do not eject ink, resulting in a loose powder structure. The results of tests including porosity, surface roughness, Micro CT scanning, mechanical properties, and in vitro drug release of the printed product indicate that the personalized ODTs with complex structures designed in this study can offer treatment solutions for specific populations.

Needle-Free Injection Technology (NFIT), which administers medication through a high-pressure transdermal jet, is limited to a delivery volume of no more than 1 mL due to device constraints. This poses challenges for the administration of poorly water-soluble drugs. Despite its potential for intramuscular delivery of nanocrystal drugs, research in this area is scarce, particularly regarding the exploration of the injection process and outcomes at the intramuscular depth. We developed solution and nanosuspension formulations of the poorly water-soluble drug midazolam and assessing their effectiveness following NFIT and needle injection administration. Our systematic evaluations encompass the velocity of needle-free injection, the establishment of a gel model for visualizing distribution, and documentation of the needle-free injection process, distribution range, impact of needle- free injection on nanocrystals' size and tissue injury, as well as a comprehensive pharmacokinetic study. Our systematic evaluation confirmed that the nanocrystals retained their physicochemical properties following needle-free injection, ensuring consistent therapeutic efficacy. A significant finding was the faster time to maximum concentration (Tmax) observed with the NFIT-administered nanosuspension (11.67 +/- 5.16 min) compared to both the needle injection of nanosuspension (32.50 +/- 22.08 min) and the NFIT-administered solution (32.50 +/- 14.75 min). Additionally, the needle-free method extended the residence time of the nano- suspension formulation. This research enhanced our understanding of NFIT and underscored its synergistic potential when combined with nanosuspensions for intramuscular drug delivery. Our findings present NFIT as a viable, less injury and rapidly effective alternative to traditional needle injections, especially offering a promising approach for the administration of midazolam nanosuspension.

As an emerging technology, 3D printing facilitates the fabrication of complex preparations and enables controlled drug release. This study integrated semi-solid extrusion (SSE) and fused deposition modeling (FDM) to develop core-shell structured sustained-release tablets (CSRT) with varying release profiles, exploring how structural design influences release behavior. Propranolol hydrochloride was selected as the model drug. Drug-loaded cores with different filling rates were prepared using SSE and characterized for appearance, hardness, XRD, and release properties. Shells with varying release windows were fabricated using FDM. Subsequently, shells and cores were assembled. Micro-CT was employed for microstructural characterization, while drug assay and release properties were assessed. The results indicated that cores exhibited a good appearance, and the SSE process had no effect on the crystal type. Adjusting the filling rate allowed for slight modulation of drug release while the shell structure effectively prolonged drug release. The CSRT displayed no significant internal defects, and the assay met the United States Pharmacopoeia-National Formulary 2024 (USP-NF 2024) requirements. Adjusting release windows resulted in a sustained release ranging from 8 to 24 h, with the release profile conforming to first-order kinetics (R2 values ranging from 0.961 to 0.999). These findings provide practical strategies for controlling drug release rates.

Low delivery efficiency and accompanying systematic toxicity of therapeutic agents have affected the efficacy of chemotherapy for osteosarcoma (OS). Meanwhile, the chemotherapy based on cisplatin, as the single modality, has reached the limits. Here, we designed a liposome nanotheranostic platform that combined cisplatin with decitabine to simultaneously activate the pyroptosis and immunogenic cell death in an effective delivery manner. Specifically, we prepared the targeted liposomal therapeutics (NPCD@ALN). NPCD@ALN effectively accumulated at the bone lesion induced by OS in vivo. Meanwhile, NPCD@ALN released NPCD and ALN when reaching the acidic tumor microenvironment, thus the charge reversing from negative to positive and enabling the better endocytosis of NPCD. NPCD activated caspase-3 to cleave GSDME into pore-forming GSDME-N terminal, letting the cancer cell release pro-inflammatory factors into the extracellular microenvironment. Subsequently, the released inflammatory cytokines promoted the maturation of antigen-presenting cells, the infiltration of cytotoxic T cells and the remodeling of immunosuppressive microenvironment. Eventually, NPCD triggered pyroptosis and immunogenic cell death and evoked the adaptive immune response to realize the powerful synergistic chemotherapy and immunotherapy for osteosarcoma. To summarize, this study exemplified rational therapeutics which facilitated the activation of pyroptosis and antitumor immune response by targeted liposomal cisplatin, and provided innovative combined-therapeutic strategies for osteosarcoma.

The management of the acute bacterial infections in the traumatic skin remains a significant challenge in clinical. The application of antibiotics on wounds is typically avoided due to antimicrobial resistance risks. Antisense therapeutics, like antisense oligonucleotides (ASOs), present a selective, low-resistance alternative, but effective bacterial uptake is still a major obstacle. In this work, we developed a novel microneedle-based delivery system (MNDS) distinguished by its distinctive multifunctional hydrogels and a "Tripartite Delivery" mechanism. The MNDS was designed with a bionic mushroom-shaped multilayered structure. Upon application, the MNDS enabled an initial rapid release and sustained release of the encapsulated nanocomplexes (ASO@GP-SiNPs). The needle body layer hydrogels can respond to hyaluronidase and continuously release hyaluronic acid and epsilon-polylysine for several days. These ASO@GP-SiNPs were effectively uptaken by E. coli (46.4 %) and S. aureus (37.1 %), subsequently releasing ASOs that target the acpP and ftsZ genes to effectively eliminate bacteria. The system exhibits significant antibacterial activity and effectively inhibits biofilm formation, while also inducing the polarization of macrophages toward an M2-like phenotype. Additionally, the system demonstrates excellent biocompatibility. In conclusion, this paper presents a novel strategy for addressing the challenges of acute bacterial infections in traumatic skin by utilizing the advanced functionalities of MNDS.

Compared with conventional transdermal drug delivery systems, dissolving microneedles significantly enhance drug bioavailability by penetrating the stratum corneum barrier and achieving intradermal drug delivery. In order to improve the transdermal bioavailability of dexmedetomidine hydrochloride, in this study, a novel microneedle delivery system was developed for dexmedetomidine hydrochloride based on 3D printing combined with micro-molding. By systematically optimizing the microneedle geometrical parameters, array arrangement, and preparation process parameters, we determined the optimal ratio of drug-carrying matrix as 15% PVP (polyvinyl pyrrolidone) K90. The microneedles exhibited significant drug loading gradients, with mean content of (209.99±27.56) μg/patch, (405.31±30.31) μg/patch, and (621.61±34.43) μg/patch. They showed a regular pyramidal structure under SEM and handheld electron microscopy, and their mechanical strength allowed effective penetration into the stratum corneum. The surface contact angles were all < 90°, indicating excellent hydrophilicity. The microneedles dissolved completely within 10 min after skin insertion, achieving a cumulative release rate of 90% (Higuchi model, r=0.996) during 2 hours of in vitro transdermal permeation. The cytotoxicity test and hemolysis test verified good biocompatibility. Pharmacodynamic evaluation showed that the microneedle group demonstrated pain-relieving effect within 15 min, with the pain threshold at the time point of 60 min being 3 times that in the transdermal cream group. The microneedle system developed in this study not only offers an efficient drug delivery option for patients but also establishes an innovative platform for rapid percutaneous delivery of hydrophilic drugs, demonstrating significant potential in perioperative pain management.

The application of binder jet 3D printing technology in the pharmaceutical field is developing rapidly. The properties of the ink are very important, affecting the stability of the ejection and the precision of the finished product, but there is a great lack of research on pharmaceutical inks. This study used solvents and excipients commonly used in pharmaceuticals to quantify the printability of inks using printability Z value theory, while using an ink-jet printing and observation platform to analyze the droplet ejection state of different composition inks from microscopic level. Studies have shown that compared to ethanol, the ejection effect of droplets was better when isopropanol was added to the ink, and the proportion added should not be greater than 40%; as the molecular weight of polyvinylpyrrolidone (PVP) increased, the concentration of PVP tolerated by the ink decreased; glycerin has a high ejection efficiency when the proportion is within 10%. In summary, a superior ink formulation of 40% aqueous isopropanol plus 0.1% PVP K30 and 4% glycerin was obtained. With this ink, levetiracetam dispersible tablets were prepared with a smooth printing process and the tablets had good appearance, good mechanical properties, and rapid release. This study provides a mutual validation of the Z value theory and the results of droplet ejection and tablet printing, while providing good ideas.

Mucosal vaccines can prevent viruses from infecting the respiratory mucosa, rather than only curtailing infection and protecting against the development of disease symptoms. The SARS-CoV-2 spike receptor-binding domain (RBD) is a compelling vaccine target but is undermined by suboptimal mucosal immunogenicity. Here, we report a SARS-CoV-2-mimetic extracellular-vesicle vaccine developed using genetic engineering and dendritic cell membrane budding. After mucosal immunization, the vaccine recruits antigen-presenting cells rapidly initiating a strong innate immune response. Notably, it obviates the need for adjuvants and can induce germinal center formation through both intramuscular and intratracheal vaccination. It not only elicits high levels of RBD-specific antibodies but also stimulates extensive cellular immunity in the respiratory mucosa. A sequential immunization strategy, starting with an intramuscular injection followed by an intratracheal booster, significantly bolsters mucosal immunity with high levels of IgA and tissue-resident memory T cell responses, thereby establishing a formidable defense against pseudovirus infection.

The treatment of wounds in subtropical coastal areas presents unique environmental challenges. Infection prevention, light-induced damage management, and wound fluid control are crucial considerations for effective wound healing. Herein, this study aimed to fabricate a novel bilayered Janus wound dressing by in situ electrospinning technology, designed to exhibit excellent resistance to UV radiation, robust antibacterial property, and efficient fluid management capability. To realize the directional liquid transport function of Janus bilayer dressing, we selected a poly(vinyl butyral) (PVB) hydrophobic inner layer and a poly(vinyl alcohol) (PVA) hydrophilic outer layer as the base material. Antibacterial drugs were introduced through the PVB layer, with the aim of achieving antibacterial function. SiO2 was introduced through the PVA layer to realize the antiultraviolet radiation effect. By adjusting the amount of drug and SiO2, multifunctional PVB@Amp&PVA@SiO2 composite dressings were systemically optimized with good antibacterial properties (more than 96% against both Escherichia coli and Staphylococcus aureus), excellent resistance to ultraviolet radiation (UPF up to 55.78), and unidirectional exudate exportation of tissue fluid from the wound to the outside world in 4 min. Moreover, the composite dressing had good biocompatibility, including a 95.64% cell survival rate and a 0.0929% hemolysis rate. This study provided a promising new option for antibacterial and ultraviolet radiation protection in subtropical coastal environments with promising applications in outdoor first aid, wound care, and military products.

Microneedles (MNs) penetrate the stratum corneum and reach the epidermis, bypassing nerve fibers and providing a precise and controlling pathway for the delivery small molecule drugs, proteins, and nucleic acid drugs. This approach minimizes pain and tissue damage during penetration, facilitating autonomous administration. Emerging 3D micro-nano printing technologies offer innovative fabrication strategies for MNs. In addition to enhanced printing resolution, 3D printing allows flexibility in prototype design and manufacturing methods, enabling the fabrication of complex structure MNs or polydimethylsiloxane (PDMS) molds with excellent repeatability and effectiveness. Recently, several micro-nanoscale 3D printing technologies, such as projection micro stereolithography (PμSL) and two-photon polymerization (TPP), have been integrated into various stages of MNs manufacturing. This review aims to provide a comprehensive overview of diverse strategies for drug release and delivery modes using MNs, and a specific focus on analyzing advancements in 3D micro-nano printing technologies. It emphasizes the pivotal role played by 3D printing in the field of MNs and specifically discusses future research directions and emerging trends in this domain.

After decades of development, hot melt extrusion (HME) technology has matured as a well-established pharmaceutical methodology. Through the process of extruding both drug and carrier materials in a molten state under specific conditions of pressure, velocity, and screw design, this technology facilitates the dispersion of the drug within the carrier in various states such as molecular, amorphous, or sub-stable, thereby significantly improving the solubility and bioavailability of challenging drugs. Currently, over 20 drugs have obtained FDA approval for production and formulation via hot-melt extrusion, underscoring the demonstrated effectiveness and dependability of this technique. This review aims to offer an in-depth examination of the principles, benefits, and applications of hot-melt extrusion in pharmaceutical science, with a particular focus on the key determinants that impact the success of hot-melt extrusion. Additionally, it aims to explore the future applications and potential developmental opportunities of this technology, with an emphasis on its utility for continuous manufacturing (CM) and personalized drug delivery.

Since the first three-dimensional (3D) printed drug was approved by the Food and Drug Administration in 2015, there has been a growing interest in using binder jet 3D printing (BJ-3DP) technology for pharmaceuticals. However, most studies are still at an exploratory stage, lacking micromechanism research, such as the droplet ejection mechanism, the effect of printhead piezoelectric parameters on inkjet smoothness and preparation formability. In this study, based on the inkjet printing and observation platform, the Epson I3200-A1 piezoelectric printhead matched to the self-developed BJ-3DP was selected to analyze the droplet ejection state of self-developed ink at the microlevel with different piezoelectric pulse parameters. The results showed that there was a stable inkjet state with an inkjet pulse width of 3.5 μs, an ink supply pulse width of 4.5 μs, and a jet frequency in the range of 5000-19,000 Hz, ensuring both better droplet pattern and print accuracy, as well as high ejection efficiency. In conclusion, we performed a systematic evaluation of the inkjet behavior under different piezoelectric pulse parameters and provided a good idea and case study for the optimization of printhead piezoelectric parameters when BJ-3DP technology was used in pharmaceuticals.

Currently, there is a shortage of pediatric medicines on the market, and 3D printing technology can more flexibly produce personalized medicines to meet individual needs. The study developed a child-friendly composite gel ink (carrageenan-gelatin), created 3D models by computer-aided design technology, then produced personalized medicines using 3D printing to improve the safety and accuracy of medication for pediatric patients. An in-depth understanding of the printability of different formulations was obtained by analyzing the rheological and textural properties of different gel inks and observing the microstructure of different gel inks, which guided the formulation optimization. Through formulation optimization, the printability and thermal stability of gel ink were improved, and F6 formulation (carrageenan: 0.65%; gelatin: 12%) was selected as the 3D printing inks. Additionally, a personalized dose linear model was established with the F6 formulation for the production of 3D printed personalized tablets. Moreover, the dissolution tests showed that the 3D printed tablets were able to dissolve more than 85% within 30 min and had similar dissolution profiles to the commercially available tablets. This study demonstrates that 3D printing is an effective manufacturing technique that allows for flexible, rapid, and automated production of personalized formulations.

微针是一种新型的透皮给药方式,因具有无痛、生物利用度高及易给药等特点而被广泛关注.介绍了微针的分类和释药机制、光固化3D打印微针技术的原理和优缺点及其应用,重点分析了光固化3D打印微针在皮肤疾病治疗、胰岛素递送、癌症治疗和美容医疗方面应用的研究进展,阐述了光固化3D打印微针具有可以显著提高药物经皮渗透率、提高给药精确性、减少全身副作用的独特优势.最后,对光固化3D打印微针当前面临的材料生物相容性差、载药量低和现行法规不完善等问题进行探讨,并对其发展前景进行了展望.