Ferroptosis, a regulated cell death pathway characterized by iron dysregulation and lipid peroxide accumulation, has emerged as a pivotal target in the treatment of cancer and other diseases. As a natural iron storage protein in organisms, ferritin (Fn) is involved in regulating intracellular iron homeostasis through processes such as iron transport, storage, and ferritinophagy, which in turn significantly influence the Fenton reaction, making it closely related to the occurrence of ferroptosis. Additionally, due to the unique cavity structure of ferritin nanocages, their excellent biocompatibility and their specific binding ability for the highly expressed transferrin receptor 1 (TfR1) on the surface of tumor cells, ferritin nanocages have been extensively explored in the design and development of drug delivery systems (DDS). Given the above background, this paper reviews the novel mechanisms of ferroptosis and the research advancements in the related diseases and drugs. It further explores the structure and application of ferritin (including DDS design and vaccine development) and emphasizes the construction of DDSs regulating ferroptosis through utilizing ferritin nanocages as carriers or by targeting the disruption of endogenous ferritin, with the expectation of providing a reference for the development of safer and more effective nanoformulations.

Direct delivery of the Cas9/sgRNA ribonucleoprotein (RNP) via appropriate carriers has been proved to be an important advance for the in vivo translocation and gene editing of CRISPR/Cas9. These carriers often require the nuclear localization signal (NLS) to fuse with Cas9 or the NLS-bearing protein to form a complex with Cas9 to enter the nucleus. In this study, we introduced apoferritin nanocages as carriers and DOX as a nuclear trigger for the nuclear transport of the Cas9/sgRNA ribonucleoprotein without the NLS (RNP-). Our experiments showed that loading RNP- and DOX into 4L-FTH subunit-based apoferritin nanocages leads to efficient endocytosis and lysosomal escape. Specifically, when DOX was administered at a concentration of 1 μM, we observed the activation of cellular defense mechanisms, which effectively facilitated the translocation of 4L-HFn@RNP-/DOX nanoparticles into the nucleus, thereby enabling intranuclear RNP- delivery. This strategy has been empirically demonstrated to achieve gene editing efficiencies of approximately 33% for the Lcn2 gene in MDA-MB-231 cells and 17.9% for the copepod green fluorescent protein (copGFP) gene in HeLa.copGFP cells in vitro. Moreover, in vivo editing efficacy, as tested in a HeLa.copGFP nude mouse model, was confirmed to be 16%. This delivery system presents a novel therapeutic approach for the nuclear delivery of small molecules or nucleic acid drugs, potentially overcoming the challenges associated with nuclear entry barriers.

Calcium overload is an emerging tumor treatment strategy that induces cell death by disrupting the homeostasis of calcium ions (Ca2+) in tumor cells. In this study, we have engineered a novel polymerized apoferritin carrier, utilizing reversible boronate ester bonds to interconnect the dihydrocaffeic acid modified ε-polylysine (ε-PLL-CAT) and 3-formylphenylboronic acid (3-FPBA) modified on the surface of individual apoferritin. This carrier is further compartmentalized with calcium phosphate and the calcium ion extrusion inhibitor curcumin. We have confirmed that during in vivo circulation, polymerized apoferritin can effectively reduce the interception and interference of the nanocage by masking the long unstructured loop on the surface of the apoferritin nanocage. Upon encountering the acidic tumor microenvironment, the reversible boronate ester bonds gradually degrade, triggering the progressive disassembly of the polymerized protein cage. This process culminates in the release of a high concentration of intracellular calcium ions within tumor cells, thereby significantly enhancing the efficacy of calcium overload therapy for breast cancer. Moreover, these dispersed nanocages can trigger a domino effect in neighboring tumor cells, facilitating deep-layer delivery. This process is mediated by calcium ion-dependent lysosomal exocytosis and transcytosis, which has been shown to be highly beneficial for inducing calcium overload. In summary, the strategy presented in this study not only improves the in vivo biodistribution of apoferritin nanocages for drug delivery, but also considerably broadens their potential applications in calcium overload therapy for tumors.

The treatment of solid tumors often faces significant hurdles. These include inefficient drug delivery due to a lack of specific targets and difficulties in penetrating tumors, as well as inadequate immune activation exacerbated by immunosuppressive tumor microenvironments. This study introduces a biomimetic system that employs a fusion membrane (FM) composed of hyaluronidase-decorated bacterial-derived outer membrane vesicles (OMVs) and PD-L1 knockout cancer-derived cell membranes (CCMs). By leveraging the affinity of the OMVs for neutrophils, the FMs can efficiently navigate to tumor sites. The hyaluronidase decoration further overcomes the fibrotic matrix barrier, facilitating the infiltration of immune cells and therapeutic agents. Meanwhile, the genetically edited CCMs not only ensure precise homologous tumor targeting but also minimize the introduction of exogenous immunosuppressive factors. Each component of the FM provides an abundance of antigens, amplifying immune enhancement and addressing the issue of inadequate immune responses. In multiple tumor models, our results demonstrated that FM system exhibited superior tumor targeting, penetration, and immune activation. When combined with chemotherapy and immunotherapy, it led to significant tumor volume reduction and survival benefits. This advanced biomimetic platform integrates precise targeting, efficient drug delivery, and potent immune stimulation, offering a promising approach for solid tumor treatment.

Introduction: Protein sorting within mitochondria is intricately linked to the amino acid sequence facilitating the transmembrane transport of proteins into this organelle. Leveraging the Mitochondrial Targeting Signal (MTS)-mediated protein sorting mechanism presents a promising strategy for directing therapeutic agents into the mitochondria. Objectives: By fusing MTS to the subunit terminus of recombinant heavy chain ferritin (HFn), we aim to establish a highly effective mitochondrial targeting vector. This fusion is designed to enhance the ability to specifically direct and accumulate within mitochondria, and to precisely deliver Lonidamine (LND), a selective metabolic inhibitor, into these organelles, ultimately realizing potent anti-tumor activity. Methods: Utilizing gene engineering strategies, a plasmid encoding MTS-modified HFn (MTS-HFn) was transferred into E.coli to induce protein expression. At the cellular level, the mitochondrial targeting capacity of MTS-HFn was investigated. Subsequently, LND was encapsulated within MTS-HFn, and its tumoral accumulation and anti-tumor efficacy were studied in tumor-bearing models. Results: MTS-HFn demonstrated exceptional mitochondrial targeting, achieving a 2.7-fold higher accumulation in mitochondria compared to wild-type HFn. The targeting mechanism exploration unveiled that the positive charge of MTS drives aggregation of HFn around mitochondria, and mediates its entry into the mitochondrial matrix via the TOM/TIM complex. In vivo antitumor activity studies revealed that MTS-HFn preserved its inherent tumor targeting ability and significantly enhanced the tumor suppressive effect of LND, yielding an inhibition rate of 51.06%. Conclusion: This vector inspired by natural mitochondrial protein sorting represents an optimal hierarchical delivery system for targeting both tumor and mitochondrial, offering a dependable alternative for precise treatment strategies in mitochondrial diseases.

Diabetic wounds, a common complication of diabetes, pose significant challenges in clinical management. Proactively targeting bacterial biofilms in chronic wounds can enhance anti‐inflammatory efficacy, accelerate the transition from inflammation to tissue proliferation, and promote more efficient healing. In this study, a bilayer hydrogel patch (NIM@UP/CuS@BT gel) is developed for diabetic wound management. This innovative system comprises a glucose‐responsive bottom layer containing copper sulfide (CuS) to deliver transient antibacterial and antibiofilm activity during the initial infection phase, and a stable upper layer incorporating nimesulide (NIM) to provide sustained anti‐inflammatory effects throughout the subsequent healing phase. This results demonstrate that the upper layer of the hydrogel patch exhibits enhanced mechanical strength of 146.3 ± 18.9 kPa, offering robust physical protection similar to a plaster. Additionally, the patch exhibits satisfied antibacterial performance, achieving over 95% bactericidal efficacy against both Escherichia coli ( E. coli ) and Staphylococcus aureus ( S. aureus ), with an in vivo bactericidal rate of 78.7%. Furthermore, the downregulation of pro‐inflammatory cytokines tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) and the upregulation of the anti‐inflammatory cytokine interleukin‐10 (IL‐10) confirms its potent anti‐inflammatory properties. In summary, the bilayer hydrogel system exhibits high biocompatibility, antibacterial and anti‐inflammatory capabilities, addressing the distinct needs of different stages in the wound healing process.

Periodontitis, a prevalent chronic oral disease, poses a significant threat to periodontal tissues, often resulting in substantial attachment loss and tooth shedding. Leveraging the principles of bone affinity and the mechanism underlying tetracycline pigmentation of teeth, this study strategically employed tetracycline (TC) as a bone-affinity group. We modified TC on the surface of polylactic-co-glycolic acid copolymer (PLGA) microspheres (MSs) through covalent binding, and then loaded berberine (BBR) MSs into a thermosensitive self-healing hydrogel delivery system (BBR/TC-MS). It was verified that the BBR/TC-MS gel rapidly formed an in situ reservoir in the periodontal pocket upon injection, and the chelation between TC and cementum in the periodontal pocket enhanced the anchoring effect of the TC-modified microspheres on cementum, preventing their loss through gingival crevicular fluid. Subsequently, we proved in vitro and in vivo that the BBR/TC-MS gel has excellent bacteriostatic effects against the periodontal pathogenic bacteria Fusobacterium necrophorum (Fn), anti-inflammation property in periodontal and gingival tissues, and osteogenic effect by regulating the RANKL-RANK-OPG pathway to diminish osteoclast activity, thus continuously exerting antibacterial, anti-inflammatory, osteogenic, and anti-osteoclastic effects. This innovative approach holds promise as a targeted and effective strategy for combating multifaceted challenges posed by periodontitis. Periodontitis, a prevalent chronic oral disease, poses a significant threat to periodontal tissues, often resulting in substantial attachment loss and tooth shedding.

The importance of copper homeostasis in mitochondria and copper-triggered modality of mitochondrial cell death have been confirmed. However, the existing copper-based nanoplatforms are focused on synergistic therapies while the intracellular therapeutic targets are relatively scattered. Effective integration of all targets within mitochondria to generate power coalescence remains a challenge. Herein, we developed a novel copper-based delivery system to trigger power coalescence and death vortex within tumor cell mitochondria. Specifically, a mitochondrial targeting "copper missile" loaded with curcumin (termed as Cur@CuS-TPP-HA, CCTH) was designed for cuproptosis/phototherapy/chemotherapy synergistic anti-tumor therapy. Once the CCTH NPs are shuttled to the mitochondria, near-infrared (NIR) irradiation initiates the release of copper ions and curcumin for in situ drug accumulation in cancer cell mitochondria. An excess of copper ions and curcumin can activate cuproptosis and mitochondrial apoptosis pathways, respectively. When combined, they can cause an increase in reactive oxygen species (ROS), damage to mitochondrial DNA (mt-DNA), and a decrease in energy supply, thereby leading to a "vicious circle" of mitochondrial damage that further enhances the tumor-killing efficacy. As a consequence, this "copper missile" exhibits advanced anti-tumor effects as verified through in vitro assessments and in vivo evaluations using the 4T1 breast tumor model, providing a promising approach for cuproptosis-based synergistic anti-tumor therapy.

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Hydroxychloroquine sulfate (HCQ) is currently being repurposed for cancer treatment. The antitumor mechanism of HCQ is inhibition of cellular autophagy, but its therapeutic potential is severely limited by poor solubility, lack of tumor targeting and lower cellular uptake. Therefore, utilization of human H-chain apoferritin (HFn) composed only of heavy subunits is an attractive approach for tumor targeting drug delivery. This study focused on pH-triggered encapsulation of HCQ within the inner cavity of HFn to form HFn@HCQ nanoparticles for tumor-targeted drug delivery. Characterization using a range of techniques has been used to confirm the successful establishment of HFn@HCQ. HFn@HCQ exhibited pH-responsive release behavior, with almost no drug release at pH 7.4, but 80% release at pH 5.0. Owing to its intrinsic binding to transferrin receptor 1 (TfR1), HFn@HCQ was significantly internalized through TfR1-mediated endocytosis, with a 4.4-fold difference of internalization amount across cell lines. Additionally, HFn@HCQ enhanced the antitumor effect against four different cancer cell lines when compared against HCQ alone, especially in TfR1 high-expressing cells, where the inhibitory effect was 3-fold higher than free HCQ. The autophagy inhibition of HFn@HCQ has been demonstrated, which is a major pathway to induce cancer cell death. According to current findings, HFn based drug delivery is a promising strategy to target and kill TfR1 overexpressing tumor cells.

Cancer remains one of the deadliest diseases, and is characterised by the uncontrolled growth of modified human cells. Unlike infectious diseases, cancer does not originate from foreign agents. Though a variety of diagnostic procedures are available; their cost-effectiveness and accessibility create significant hurdles. Non-specific cancer symptoms further complicate early detection, leading to belated recognition of certain cancer. The lack of reliable biomarkers hampers effective treatment, as chemotherapy, radiation therapy, and surgery often result in poor outcomes and high recurrence rates. Genetic and epigenetic mutations play a crucial role in cancer pathogenesis, necessitating the development of alternate treatment methods. The advent of CRISPR/Cas9 technology has transformed molecular biology and exhibits potential for gene modification and therapy in various cancer types. Nonetheless, obstacles such as safe transport, off-target consequences, and potency must be overcome before widespread clinical use. Notably, this review delves into the multifaceted landscape of cancer research, highlighting the pivotal role of nanoparticles in advancing CRISPR/Cas9-based cancer interventions. By addressing the challenges associated with cancer diagnosis and treatment, this integrated approach paves the way for innovative solutions and improved patient outcomes

The Ins/Ur/MgO@SA microsphere exhibits rapid settling in the stomach and deep penetration into the mucus layer via urease-catalyzed urea hydrolysis, thereby enhancing the bioavailability of macromolecular drugs by overcoming acid, enzyme, and mucus barriers in the gastric environment.

Mesenchymal stem cells (MSC) are particularly effective in promoting cartilage regeneration due to their immunomodulatory, anti-inflammatory and regenerative repair functions of tissues and organs. Meanwhile, the intra-articular delivery and synergy with other therapeutic drugs have been the key issues driving their further application. We report a mussel-inspired multifunctional hydrogel system, which could achieve co-delivery and synergism effect of MSC-derived exosomes (Exos) with icariin (ICA). The ICA and Exos co-delivered articular cavity injection system are expected to retain in the joint cavity and promote cartilage regeneration, due to the thermosensitive, self-healing and adhesion properties of the mussel-inspired multifunctional hydrogel. The experimental results proved that Exos enhanced the cellular uptake of ICA by more than 2-fold evenly, and the synergism of Exos and ICA efficiently improve the cell proliferation and migration. After synergic treatment, the content of matrix metalloproteinase 13 in the supernatant and intracellular decreased by 47% and 59%, respectively. In vivo study, ICA-loaded Exos exhibited prolonged retention behavior by multifunctional hydrogel delivery, thus displayed an increased cartilage protection. In the model of osteoarthritis, co-delivery hydrogel system relieved the cartilage recession, ensuring appropriate cartilage thickness.

Ferroptosis is a new type of cell death discovered in recent years that distinguishes from apoptosis and necrosis, mainly caused by the imbalance between the production and degradation of lipid reactive oxygen species in cells. Although the mechanism of ferroptosis is not yet clear, the phenomenon of ferroptosis has attracted widespread attention from researchers and has become a new hotspot in anti-tumor research. Studies have shown that ferroptosis is involved in the occurrence and development of a variety of diseases such as nervous system diseases, cardiovascular diseases and cancer. And inhibiting or inducing the occurrence of ferroptosis can effectively intervene in related diseases. At the same time, nanotechnology, by virtue of its distinct advantages, has been widely used in the development of nanodrug delivery systems. This review outlines current the advance on the intersection of ferroptosis and biomedical nanotechnology. In this review, the discovery and characteristics of ferroptosis, the mechanism of occurrence and the relationship with disease are summarized. More importantly, we summarized the strategies for inducing ferroptosis based on nanoparticulate drug delivery systems for cancer treatment.

Commonly, most oral non-steroidal anti-inflammatory drugs (NSAIDs) have known gastric adverse reactions due to their long-term and high dose administration. In this study, a novel liquid sustained-release system based on multiple-unit in situ hydrogel beads was designed to address this issue. The system is composed of sodium alginate (SA), gellan gum (GG), zinc oxide (ZnO), and magnesium oxide (MgO). Furthermore, indobufen was loaded into the system to evaluate its gastric mucosal protection effect. This effect can be attributed to the topical antacid, pepsin inhibition, and sustained drug release properties of the system. It was proven that the stored solid gel system could undergo a "solid to liquid" transition after shaking. Once swallowed, the liquid gel could disperse well in the stomach as hydrogel beads. Then, the "liquid to solid" gelation occurred from the exterior to interior of each multiple-unit gel bead, triggered by the release of Zn2+ and Mg2+ from neutralization reactions. The formed gel demonstrated mild antacid effect that lasted for 3 hours and 66.3% pepsin inhibition in vivo. Moreover, the rats treated with the indobufen gel system showed a drug plasma concentration versus time curve with less fluctuation compared to the rats treated with the marketed preparation (YinDuo®) group. The gel system also exhibited an extended Tmax (6.50 hours) and reduced Cmax (52.87 μg/mL). Additionally, the gastric mucosal protection of the gel system was verified using three types of peptic gastric ulcer models. These findings suggested that this multiple-unit in situ gel could be a potential oral liquid sustained release delivery system for NSAIDs.

目的:研究比对不同配方的窄治疗指数药物多西他赛注射液配制的临床给药溶液胶束的性质.方法:选取不含乙醇的多西他赛注射液国产产品与含乙醇的原研参比制剂,对稀配后药液中所形成的胶束性质进行对比研究.结果:两种产品利用不同介质(0.9％NaCl注射液、5％葡萄糖注射液)稀配后得到的药液中,增溶剂的临界胶束浓度值无显著差异;胶束的平均粒径、分散系数基本一致;且2种产品稀配所形成胶束的稳定性均良好.结论:不同辅料的产品中增溶剂在稀配过程中均形成了稳定胶束,起到增加主药溶解度的作用.

Background:Synergistic chemotherapy has been proved as an effective antitumor means in clinical practice. However, most co-administration treatment often lacks simultaneous control over the release of different chemotherapeutic agents.Materials and Methods:β-cyclodextrin modified hyaluronic acid was the "shell", and the oxidized ferrocene-stearyl alcohol micelles served as the "core", where doxorubicin (DOX) and curcumin (CUR) were loaded in shell and core of the bilayer nanoparticles (BNs), respectively. The pH- and glutathione (GSH)-responsive synchronized release behavior was evaluated in different mediums, and the in vitro and in vivo synergistic antitumor effect and CD44-mediated tumor targeting efficiency were further investigated.Results:These BNs had a spherical structure with the particle size of 299 ± 15.17 nm, while the synchronized release behaviour of those two drugs was proved in the medium with the pH value of 5.5 and 20 mM GSH. The co-delivery of DOX and CUR reduced the IC50 value by 21% compared to DOX alone, with a further 54% reduction after these BNs delivery measurements. In tumor-bearing mouse models, these drug-loaded BNs showed significant tumor targeting, enhanced antitumor activity and reduced systemic toxicity.Conclusion:The designed bilayer nanoparticle could be considered as potential chemotherapeutic co-delivery platform for efficient synchronized microenvironment respond and drug release. Furthermore, the simultaneous and synergistic drug release guaranteed the enhanced antitumor effects during the co-administration treatment.

为提升药学专业教学质量,培养适应时代的药学人才,对比中国药科大学和莫纳什大学在课程设置、教学手段、技能训练等方面的异同,以期为教学改进提供参考.

铁死亡是一种有别于细胞凋亡的铁依赖性细胞死亡方式.目前发现的铁死亡诱导药物主要有胱氨酸/谷氨酸反向转运体抑制剂、谷胱甘肽过氧化物酶4(GPX4)抑制剂和芬顿(Fenton)反应诱导剂3大类,可通过多种途径或靶点诱导癌细胞铁死亡,对已产生多药耐药的恶性肿瘤细胞亦具有良好杀伤潜力,如通过直接或间接影响GPX4而抑制GPX4蛋白水平和活性、诱导芬顿反应氧化Fe2+或促进脂质过氧化物积聚等机制诱导铁死亡.本文综述铁死亡诱导药物及其抗癌机制,为探索基于铁死亡的癌症治疗策略及抗癌制剂开发提供有益参考.