Acute lung injury (ALI) is a common critical illness driven by uncontrolled pulmonary inflammation, with hyperactivated macrophages sustaining pro-inflammatory cytokine release. Activation of liver X receptor α (LXRα) can suppress inflammatory gene expression. However, clinical translation of LXRα agonists such as T0901317 (T09) is limited by off-target effects, particularly hepatotoxicity. Here, we developed a biomimetic controlled-release platform (AB/NPs@T09) using mesenchymal stem cell (MSC)-derived apoptotic bodies (ABs) as natural carriers for T09. The structural properties of ABs facilitated macrophage uptake via the efferocytosis pathway. Inhalation administration of AB/NPs@T09 enabled dual organ-cell targeting, increasing pulmonary drug accumulation while markedly reducing liver distribution. In an ALI mouse model, inhaled AB/NPs@T09 at a low dose (1 mg/kg) achieved anti-inflammatory efficacy comparable to that of high-dose intraperitoneal injection (10 mg/kg), without inducing hepatotoxicity. The biomimetic platform presented here not only offers a new avenue for therapeutic intervention in clinical ALI, but also establishes a generalizable strategy for repurposing potent yet toxic small molecules in inflammatory diseases.

The advancement of cell-based drug delivery systems (Cell-DDS) enables precise tumor targeting. Utilizing bone marrow mesenchymal stem cells (BMSC) as carriers, transferrin (Tf)-modified BMSC (BMSCTf) were engineered via sugar metabolism replacement and click chemistry. Liposomes co-encapsulating phthalocyanine (Pc) and oxygen-carrying perfluorohexane (PFH) were integrated with BMSCTf through membrane fusion, constructing the Tf-functionalized delivery system Pc/O₂@BMSCTf. This system achieved Pc loading efficiency of 1.7 μg per 10⁵ cells and an oxygen-carrying capacity of 11.2 μg per 10⁷ cells, demonstrating active tumor targeting, significant antitumor efficacy in vitro and in vivo, and high biocompatibility. At tumor sites, localized near-infrared irradiation triggered Pc-mediated ROS generation, while the nanoliposomes provided real-time oxygen replenishment, overcoming hypoxia to potentiate photodynamic therapy (PDT). This novel stem cell-based drug delivery system represents a promising strategy for targeted tumor therapy.

Botulinum neurotoxins (BoNTs) are the most potent biological toxins discovered to date. Rapid capture and clearance of BoNTs from the bloodstream is a critical strategy for poisoning treatment. Nanobodies, with their high affinity, represent promising molecules for neutralizing BoNTs. Due to its small molecular weight, it has the limitation of a short half-life in the bloodstream. The BoNT/A-neutralizing nanobody, ciA-C2, binds to the receptor-binding domain of BoNT/A, blocking its interaction with the neuronal receptor SV2 and thereby preventing toxin entry into cells to achieve detoxification. This study leverages the nanoscale addressability of DNA origami technology. Through complementary base pairing, the BoNT/A-neutralizing nanobody ciA-C2 is displayed on a DNA origami nanostructure (DON), constructing a DON-ciA-C2 anti-BoNT/A system with prolonged half-life and spatially cooperative multivalency. The DON, measuring approximately 120 nm in size-about 30 times larger than ciA-C2-extends the half-life of the system due to its larger dimensions. The multivalent assembly of ciA-C2 on the DNA origami creates a "high-affinity" nanoscale surface. This design leverages dense regional proximity effects to significantly enhance toxin-binding efficiency and stability. Additionally, a physical barrier effect is formed, effectively shielding the receptor-binding domain of BoNT/A and preventing the toxin from accessing receptors on the cell membrane. In a mouse model of BoNT/A poisoning at 10 times the lethal dose (10 LD50), DON-ciA-C2 significantly improved survival rates to 100% in both prophylactic and therapeutic administration regimens. Moreover, it extended the effective half-life of ciA-C2 from 4 h to approximately 32 h. By orderly assembling nanobodies on DNA origami, this study creates a biomimetic nanoscale trap with triple functions-"capture, enrichment, and sequestration"-against BoNT/A. This strategy not only provides a highly efficient neutralization paradigm for anti-BoNT/A therapy but also highlights the transformative potential of DNA origami nanostructures in reshaping protein interaction interfaces for precision medicine.

Malignant glioma remains one of the most aggressive and therapy-resistant brain tumors, with limited treatment options and a poor prognosis. Overcoming the blood-brain barrier (BBB) is a major challenge for effective drug delivery. Here, we developed a triple-targeted nanodelivery system, denoted BCNU-FeSeH@EVLF, which integrates magnetic guidance, chemotactic homing, and receptor-mediated transport for enhanced brain penetration and glioma treatment. The system consists of carmustine (BCNU)-loaded, hyaluronic acid-modified superparamagnetic Fe3O4 nanoparticles with a mesoporous selenium shell (FeSeH NPs), which are further encapsulated within lactoferrin-engineered extracellular vesicles (EVLF) derived from bone marrow mesenchymal stem cells. In vitro and in vivo studies demonstrated that BCNU-FeSeH@EVLF exhibited excellent BBB-crossing ability under magnetic field exposure, targeted accumulation in glioma tissues, and pH-responsive drug release within the tumor microenvironment. Selenium and BCNU act synergistically to induce reactive oxygen species generation, DNA damage, and apoptosis, leading to potent antiglioma efficacy. Importantly, the system showed high biocompatibility and negligible systemic toxicity. This work presents a robust and safe strategy for targeted glioma therapy via a multifunctional extracellular vesicle-based platform.

Thorough understanding and accurate prediction of in vivo drug release are essential for developing long-acting microsphere systems. However, the fate of microspheres after prolonged tissue residence and the regulatory role of physiological factors remain unclear, hindering elucidation of release mechanisms. Herein, the dynamic evolution of microsphere depots and associated microenvironmental changes were studied. Beyond poly(lactic-co-glycolic acid) (PLGA) and API effects, microsphere depot behavior is partly regulated by conserved biological processes, with skeletal muscle and subcutaneous tissue employing distinct adaptive strategies to restore homeostasis. Using these insights, we developed the in vivo release predictive models (IVRPMs) that establish a true IVIVC for naltrexone PLGA microspheres. The IVRPMs demonstrated broad applicability across microspheres with different APIs and PLGA types, and showed promising translational potential in beagle and human studies. This study shifts the research paradigm from "material-dominated release" to "organism-material coevolution", addressing a key question in depot formulation fate.

Photodynamic therapy (PDT) involves the activation of photosensitizers (PSs) by visible laser light at the target site to catalyze the production of reactive oxygen species, resulting in tumor cell death and blood vessel closure. The efficacy of PDT depends on the PSs, the amount of oxygen, and the intensity of the excitation laser. PSs have been extensively researched, and great efforts have been made to develop an ideal photosensitizer. Chlorin-e6 is an FDA-approved second-generation PSs that has attracted widespread research interest in the medical field, especially with respect to antitumor and anti-inflammatory activity. Chlorin-e6 possesses the advantages of a large absorption coefficient, high strength, low residue in the body, and relatively high safety and thus has promising application prospects. Here we review the use of chlorin-e6 in PDT and discuss the prospects of further development of this technology.

Acute lung injury (ALI) is a life-threatening inflammatory disease with high morbidity and mortality. It is urgent to develop more effective therapeutic strategies against ALI. Phosphatidylserine (PtdSer) expressed on the surface of apoptotic cells not only allows for macrophage binding and recognition but also drives anti-inflammatory signaling within the macrophage. In this study, we designed an apoptotic cell-mimicry nanoparticle by decorating synthetic PtdSer on the outer face of nanoparticles. The results indicated that PtdSer-decorated poly(lactic-co-glycolic acid) nanoparticles (PSNPs) showed anti-inflammatory properties and increased macrophage phagocytosis in relative to the nondecorated poly(lactic-co-glycolic acid nanoparticles. Dexamethasone-loaded PSNPs exhibited superior anti-inflammatory activity on macrophages in vitro. In vivo studies also showed that PtdSer decoration increased the accumulation of nanoparticles in lung macrophages after pulmonary administration. Accumulation of dexamethasone-loaded PSNPs in lung macrophages effectively reduced inflammation in inflamed lungs and further alleviated ALI syndromes. In conclusion, PtdSer decoration not only endows the anti-inflammatory function to nanocarriers but also potentiates its macrophage targeting in the inflamed microenvironment, which offers an ideal drug delivery platform for ALI therapy.

With the advancements in nanotechnology and biomaterials science, the development of nanodrug delivery systems (Nano-DDSs) has provided opportunities for the realization of precise targeted treatment of malignant tumors. Liposomes have become a type of DDS with early clinical application and mature development due to their excellent tissue-targeting capacity and outstanding biocompatibility. However, several obstacles remain, such as recognition and clearance by the immune system, a short half-life, and poor tumor targeting. To address these problems, we propose a new method to transform liposomes, using fusion to reassemble the extracted natural cell membranes and artificial phospholipids to form a composite nanolipid carrier (recombined lipid nanocarriers (RLNs)). We evaluated the different types of cell membrane composite lipid nanocarriers based on parameters such as particle size, stability, drug loading and release capabilities, in vitro and in vivo tumor-targeting efficacy, and safety. The results indicated that these novel tumor cell-derived membrane fusion lipid nanocarriers exhibited promising antitumor effects and safety profiles, offering insights for precision cancer treatment. Schematic illustration of the cell membrane fusion composite lipid nanocarrier RLNs and its antitumor effects. Tumor cell-derived membrane fusion lipid nanocarriers (HeLa-RLNs) exhibit promising antitumor effects and safety profiles.

In this study, a porous polydopamine (PDA) nanoparticle-decorated β-glucan microcapsules (GMs) nanoplatform (PDA/GMs) were developed with macrophage-targeted biomimetic features and a carriers-within-carriers structure. Indocyanine green (ICG) and catalase (CAT) were subsequently co-encapsulated within the PDA/GMs to create a multifunctional nanotherapeutic agent, termed CIPGs. Furthermore, CIPGs and sinomenine (SIN) were co-loaded within a thermo-sensitive hydrogel to design an injectable delivery system, termed CIPG/SH, with potential for multi-modal therapy of rheumatoid arthritis (RA). Photothermal studies indicated that the CIPGs hold excellent photothermal conversion ability and thermal stability, as they combined the photothermal performance of both PDA and ICG. Meanwhile, the CIPGs displayed favorable oxygen self-supplying and photodynamic performance. The CIPGs showed near-infrared (NIR)-induced phototoxicity, effectively inhibiting macrophage proliferation and displaying remarkable antibacterial activity. In vitro drug release from the prepared CIPG/SH showed a controlled release pattern. Animal experiments conducted on an RA mice model confirmed that the formulated CIPG/SH exhibited significant therapeutic effects. By integrating the biological advantages, photothermal/photodynamic performance of the CIPGs, and controlled drug release performance of the thermo-sensitive hydrogels in a single delivery system, the prepared injectable CIPG/SH represents a novel versatile delivery system with great potential for multi-modal combination targeting therapy in RA.

Background:The immunotherapeutic approach utilizing Natural Killer (NK) cells for cancer treatment has garnered significant interest owing to its inherent cytotoxicity, immunomodulatory properties, demonstrated safety in in vivo studies. However, multiple immunosuppressive mechanisms in the tumor microenvironment (TME) suppress the anticancer effect of NK cells in the treatment of solid tumors. Herein, a smart NK cell drug delivery system (DDS) with photo-responsive and TME-responsive properties was designed. Methods:The NK cell DDS consists of two parts: the carrier is living NK cell with pH-low (abbreviated as NKpH) insertion peptide on its surface, the cargo is reductive-responsive nanogel (NG) encapsulated siRNA and photosensitizer (abbreviated as SP-NG), the final carrier was abbreviated as SP-NG@ NKpH. Firstly, pHLip helped artificially modified NK cell target and anchor onto cancer and exert the efficacy of cellular immunotherapy. Then, the strategy of combining photoactivation and bioreduction responsiveness achieved the precise release of cargos in cancer cells. Finally, the DDS combined the effect of the immunotherapy of NK cell, the gene therapy of siRNA, and the photodynamic therapy of photosensitizer. Results:Under near-infrared laser irradiation, SP-NG@NKpH induced an increase in reactive oxygen species (ROS) within cells, exacerbated cell membrane permeability, and allowed for rapid drug release. Within the tumor microenvironment (TME), NG exhibits highly sensitive reducibility for drug release. The SP-NG released from NK cells can be uptaken by tumor cells. When exposed to near-infrared laser irradiation, SP-NG@NKpH demonstrates significant tumor-targeting specificity and cytotoxicity. Discussion:The combined effect of the immunotherapy of NK cell, the gene therapy of siRNA, and the photodynamic therapy of photosensitizer obtained a stronger cancer killing effect in vitro and in vivo. Therefore, this versatile NK cell DDS exhibits a good clinical application prospect.

Poly(lactic-glycolic acid) (PLGA) is a biocompatible bio-scaffold material, but its own hydrophobic and electrically neutral surface limits its application as a cell scaffold. Polymer materials, mimics ECM materials, and organic material have often been used as coating materials for PLGA cell scaffolds to improve the poor cell adhesion of PLGA and enhance tissue adaptation. These coating materials can be modified on the PLGA surface via simple physical or chemical methods, and coating multiple materials can simultaneously confer different functions to the PLGA scaffold; not only does this ensure stronger cell adhesion but it also modulates cell behavior and function. This approach to coating could facilitate the production of more PLGA-based cell scaffolds. This review focuses on the PLGA surface-modified materials, methods, and applications, and will provide guidance for PLGA surface modification.

设计合成了一类可聚合固化且具有良好生物降解性能的组织黏附材料.材料使用前为单体分子,常温下呈液态,单体结构含有寡聚乳酸(OLA)片段和氰基丙烯酸酯(CA)官能团.在接触到肌体组织时,单体可通过CA官能团发生分子间聚合形成梳状聚合物并产生黏附.聚合物中的OLA侧链结构可赋予其良好的生物相容性和可降解性.合成了OLA末端分别为羧基或苄基的两种单体(OLA4-CA和OLA4 B-CA),通过核磁氢谱鉴定了单体化学结构,采用剪切拉伸强度和固化时间表征组织黏附能力,利用凝胶渗透色谱测试聚合物分子量,在体内、外模型中评价聚合物的降解性能,通过植入试验研究聚合物的生物相容性,此外,采用体外抑菌圈试验测试了材料的抑菌性能.试验结果表明:成功合成了目标单体;单体接触肌体组织可在3 min内聚合固化并产生有效的黏附能力;聚合物的降解性能与侧链OLA片段的末端羧基结构相关;优选的OLA4-CA的聚合物在小鼠体内植入模型中12 h左右即被完全降解吸收,且具有良好的生物相容性;此外,在体外抑菌试验中,材料显示出浓度依赖性的抑菌能力.这类可聚合固化材料有望进一步用于新型创伤敷料和组织粘附材料的开发.

Tumor hypoxic microenvironment can reduce the therapeutic effects of chemotherapy, radiotherapy, photodynamic therapy, immunotherapy, etc. It is also a potential source of tumor recurrence and metastasis. A biomimetic nanosystem based on zeolitic imidazolate framework 8 (ZIF8), which had multifunctions of hypoxia relief, chemotherapy, and photothermal therapy, was established to improve tumor hypoxic microenvironment and overcome the corresponding therapeutic resistance. ZIF8 enveloped with DOX and CuS nanoparticles (DC@ZIF8) was synthesized by a sedimentation method. Red blood cell membrane and catalase (CAT) were coated onto DC@ZIF8 and biomimetic nanosystem (DC@ZIF8-MEMC) was formed. The designed DC@ZIF8-MEMC had a shape of polyhedron with an average particle size around 254 nm. The loading content of DOX, CAT, and CuS was 4.9%, 6.2%, and 2.5%, separately. The release of DOX from DC@ZIF8-MEMC was pH dependent and significantly faster at pH 5 due to the degradation of ZIF8. DC@ZIF8-MEMC exhibited outstanding photothermal conversion properties and excellent antitumor effect in vitro and in vivo. Moreover, the hypoxia relief by CAT was proved to have good sensitization effect on chemo-photothermal combined therapy. DC@ZIF8-MEMC is a prospective nanosystem, which can realize great chemo-photothermal synergistic antitumor effect under the sensitization of CAT. The biomimetic multifunctional nanoplatform provides a potential strategy of chemo-photothermal synergistic antitumor effect under the sensitization of CAT.

During the development of a pharmaceutical formulation, a powerful tool is needed to extract the key points from the complicated process parameters and material attributes. Artificial neural networks (ANNs), a promising and more flexible modeling technique, can address real intricate questions in a high parallelism and distributed pattern in the manner of biological neural networks. The data mined and analyzing based on ANNs have the ability to replace hundreds of trial and error experiments. ANNs have been used for data analysis by pharmaceutics researchers since the 1990s and it has now become a research method in pharmaceutical science. This review focuses on the latest application progress of ANNs in the prediction, characterization and optimization of pharmaceutical formulation to provide a reference for the further interdisciplinary study of pharmaceutics and ANNs.

本文旨在介绍一个以科研促《药物制剂设备与车间工艺设计》实训教学设计主题.首先选用薄膜水化法制备硫辛酸胶束.然后制备具有清除活性氧作用的普鲁士蓝纳米颗粒,再以羟丙基甲基纤维素作为基质与硫辛酸胶束及普鲁士蓝纳米颗粒混合后制备复合凝胶.本实训教学设计在传统凝胶剂的剂型上融合了聚合物胶束技术及纳米酶方面的研究成果,能够帮助学生扩展纳米材料和纳米技术方面的知识,有利于学生了解科学前沿,促进培养德才兼备的"高素质应用型"药物制剂专业本科人才.

The chemical modification of materials with other polymers has become an effective strategy to improve their physicochemical properties, thus expanding their biomedical applications. In this study, a new poly-merizable system based on poly(lactic acid)-modified cyanoacrylate (PLA-CA) was developed. The liquid monomers could rapidly polymerize into solid flexible films on skin and wound surfaces. Both in vitro and in vivo tests showed that the polymer could adhere firmly to the skin and provide coverage protection. More importantly, the polymer could be easily removed on demand by rubbing with a wet cotton swab. Antimicrobial, biocompatibility, and cytotoxicity testing further demonstrated that this system has the potential to be used as a wound dressing material. This work may lead to the construction of new graft polymers, which may also be applicable to polyglycolic acid, chitosan, and other biomaterials. (c) 2021 Elsevier B.V. All rights reserved.

Poly(lactic-co-glycolic acid) (PLGA) has garnered increasing attention as a candidate drug delivery polymer owing to its favorable properties, including its excellent biocompatibility, biodegradability, non-toxicity, non-immunogenicity, and mechanical strength. PLAG are specifically used as microspheres for the sustained/controlled and targeted delivery of hydrophilic or hydrophobic drugs, as well as biological therapeutic macromolecules, including peptide and protein drugs. PLGAs with different molecular weights, lactic acid (LA)/glycolic acid (GA) ratios, and end groups exhibit unique release characteristics, which is beneficial for obtaining diverse therapeutic effects. This review aims to analyze the composition of PLGA microspheres, and understand the manufacturing process involved in their production, from a quality by design perspective. Additionally, the key factors affecting PLGA microsphere development are explored as well as the principles involved in the synthesis and degradation of PLGA and its interaction with active drugs. Further, the effects elicited by microcosmic conditions on PLGA macroscopic properties, are analyzed. These conditions include variations in the organic phase (organic solvent, PLGA, and drug concentration), continuous phase (emulsifying ability), emulsifying stage (organic phase and continuous phase interaction, homogenization parameters), and solidification process (relationship between solvent volatilization rate and curing conditions). The challenges in achieving consistency between batches during manufacturing are addressed, and continuous production is discussed as a potential solution. Finally, potential critical quality attributes are introduced, which may facilitate the optimization of process parameters.

注射用乳酸-羟基乙酸共聚物(polylactide-polyglycolide,PLGA)微球作为一种储库型释药系统,自1989年第1个产品Lupron depot获准在美国上市起,已成功用于多种疾病的治疗,具备在体内几天到几个月长时间释药的能力,可显著改善用药安全性,提升患者顺应性.体内外相关性(invitro-in vivo correlation,IVIVC)研究给微球制剂的发展带来更多可能.IVIVC可以通过微球的体外释放行为阐述体内释药的动态信息,在表征微球性能的同时减轻各阶段的工作量,对药物的研发、生产变更和监督管理等具有指导或支持作用.本文将注射用PLGA微球的释放机制、体内外释放测定涉及的常用方法和理论进行归纳总结,重点讨论了IVIVC尤其是A级IVIVC在微球制剂领域的建立及应用,为进一步的微球体内外相关性研究提供参考.

Patients prefer oral drug delivery due to its convenience and noninvasiveness. Nevertheless, a multitude of potentially clinically important drugs will not reach the market or achieve their full potential, due to their low bioavailability and instability in gastric acid. In this study, a novel oral drug delivery system based on poly-cyanoacrylate [a polymer of 2-(2-methoxyethoxy)ethyl-2-cyanoacrylate (MECA)] and hydroxypropyl methylcellulose phthalate (HPMCP) was developed and shown to permit intestinal targeting and sustained drug release. Aspirin [acetylsalicylic acid (ASA)] was selected as a model drug for atherosclerosis treatment. It was physically dissolved in liquid MECA, and the ASA-MECA matrix was then polymerized into a solid drug-loading depot in an HPMCP shell. The delivery of the drug depot in the intestine was achieved with the HPMCP shell; then the polymerized MECA (polyMECA) provided sustained drug release. The polyMECA excipient was not absorbed by the intestine due to its high molecular weight; a fluorescein-labeled assay indicated that it was excreted completely in feces after drug release. The formulation, ASA-polyMECA-HPMCP, showed good intestinal targeting and sustained drug release in vitro and in vivo. Pharmacokinetic studies indicated that this formulation improved the bioavailability of ASA relative to commercially available controls. ASA-polyMECA-HPMCP showed desirable anti-atherosclerosis efficacy in a rabbit model, with significant enhancement of atheromatous lesion stability. Biosafety tests proved the low toxicity of ASA-polyMECA-HPMCP and the polyMECA matrix. We believe that this work has provided a practical and biocompatible system for sustained intestinal drug delivery that can be applied broadly with various drugs for specific therapeutic aims.

The FDA (U.S. Food and Drug Administration) has approved only a negligible number of poly(lactide-co-glycolide) (PLGA)-based microsphere formulations, indicating the difficulty in developing a PLGA microsphere. A thorough understanding of microsphere formulations is essential to meet the challenge of developing innovative or generic microspheres. In this study, the key factors, especially the key process factors of the marketed PLGA microspheres, were revealed for the first time via a reverse engineering study on Vivitrol® and verified by the development of a generic naltrexone-loaded microsphere (GNM). Qualitative and quantitative similarity with Vivitrol®, in terms of inactive ingredients, was accomplished by the determination of PLGA. Physicochemical characterization of Vivitrol® helped to identify the critical process parameters in each manufacturing step. After being prepared according to the process parameters revealed by reverse engineering, the GNM demonstrated similarity to Vivitrol® in terms of quality attributes and in vitro release (f2 = 65.3). The research on the development of bioequivalent microspheres based on the similar technology of Vivitrol® will benefit the development of other generic or innovative microspheres.