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Pulmonary fibrosis (PF) is an interstitial lung disease with complex pathological mechanism, and there is currently a lack of therapeutics that can heal it completely. Using gene therapy with drugs provides promising therapeutic strategies for synergistically reversing PF. However, improving the intracellular accumulation and transfection efficiency of therapeutic nucleic acids is still a critical issue that urgently needs to be addressed. Herein, we developed lipid nanoparticles (PEDPs) with high transfection efficiency coloaded with pDNA of nuclear factor erythroid 2-related factor 2 (pNrf2) and pirfenidone (PFD) for PF therapy. PEDPs can penetrate biological barriers, accumulate at the target, and exert therapeutic effects, eventually alleviating the oxidative stress imbalance in type II alveolar epithelial cells (AECs II) and inhibiting myofibroblast overactivation through the synergistic effects of Nrf2 combined with PFD, thus reversing PF. In addition, we systematically engineered various liposomes (LNPs), demonstrated that reducing the polyethylene glycol (PEG) proportion could significantly improve the uptake and transfection efficiency of the LNPs, and proposed a possible mechanism for this influence. This study clearly reveals that controlling the composition ratio of PEG in PEDPs can efficiently deliver therapeutics into AECs II, improve pNrf2 transfection, and synergize with PFD in a prospective strategy to reverse PF.
Mitochondria play significant roles in maintaining a stable internal environment for cell metabolism. Hence, real-time monitoring of the dynamics of mitochondria is essential for further understanding mitochondria-related diseases. Fluorescent probes provide powerful tools for visualizing dynamic processes. However, most mitochondria-targeted probes are derived from organic molecules with poor photostability, making long-term dynamic monitoring challenging. Herein, we design a novel mitochondria-targeted probe based on carbon dots with high performance for long-term tracking. Considering that the targeting ability of CDs is related to surface functional groups, which are generally determined by the reaction precursors, we successfully constructed mitochondria-targeted O-CDs with emission at 565 nm through solvothermal treatment of m-diethylaminophenol. The O-CDs are bright with a high quantum yield of 12.61%, high mitochondria-targeting ability, and good stability. The O-CDs possess a high quantum yield (12.61%), specific mitochondria-targeting ability, and outstanding optical stability. Owing to the abundant hydroxyl and ammonium cations on the surface, O-CDs showed obvious accumulation in mitochondria with a high colocalization coefficient of up to 0.90 and remained steady even after fixation. Besides, O-CDs showed outstanding compatibility and photostability under various interruptions or long-time irradiation. Therefore, O-CDs are preferable for the long-term tracking of dynamic mitochondrial behavior in live cells. We first observed the mitochondrial fission and fusion behaviors in HeLa cells, and then, the size, morphology, and distribution of mitochondria in physiological or pathological conditions were clearly recorded. More importantly, we observed different dynamics interactions between mitochondria and lipid droplets during the apoptosis and mitophagy processes. This study provides a potential tool for exploring interactions between mitochondria and other organelles, further promoting the research on mitochondria-related diseases.
Cell-penetrating peptides (CPPs) are attractive non-viral gene delivery vectors due to their high transfection capacity and safety. Previously, we have shown that cell-penetrating peptide RALA can be a promising gene delivery vector for chronic wound regeneration application. In this study, we engineered a novel peptide called RALA-E by introducing elastin-derived VGVAPG fragment into RALA, in order to target the elastin-binding protein on the cell surface and thus improve delivery efficacy of RALA. The transfection efficiency of RALA-E was evaluated by transfecting the HEK-293T and HeLa cell lines cells with RALA-E/pDNA complexes and the flow-cytometry results showed that RALA-E significantly increased the transfection efficiency by nearly 20% in both cell lines compared to RALA. Inhibition of pDNA transfection on HEK-293T cells via chlorpromazine, genistein and mβCD showed that the inhibition extent in transfection efficiency was much less for RALA-E group compared to RALA group. In addition, RALA-E/miR-146a complexes showed up to 90% uptake efficiency in macrophages, and can escape from the endosome and enter the nucleus to inhibit the expression of inflammation genes. Therefore, the developed RALA-E peptide has high potential as a safe and efficient vector for gene therapy application.Keywords:cell-penetrating peptide;gene delivery;elastin-derived peptide;elastin-binding protein;immune modulation
Platinum (Pt) resistance in cancer almost inevitably occurs during clinical Pt-based chemotherapy. The spontaneous nucleotide-excision repair of cancer cells is a representative process that leads to Pt resistance, which involves the local DNA bending to facilitate the recruitment of nucleotide-excision repair proteins and subsequent elimination of Pt-DNA adducts. By exploiting the structural vulnerability of this process, we herein report a nuclease-mimetic Pt nanozyme that can target cancer cell nuclei and induce concurrent DNA platination and oxidative cleavage to overcome Pt drug resistance. We show that the Pt nanozyme, unlike cisplatin and conventional Pt nanoparticles, specifically induces the nanozyme-catalyzed cleavage of the formed Pt-DNA adducts by generating in situ reactive oxygen species, which impairs the damage recognition factors-induced DNA bending prerequisite for nucleotide-excision repair. The recruitment of downstream effectors of nucleotide-excision repair to DNA lesion sites, including xeroderma pigmentosum groups A and F, is disrupted by the Pt nanozyme in cisplatin-resistant cancer cells, allowing excessive accumulation of the Pt-DNA adducts for highly efficient cancer therapy. Our study highlights the potential benefits of applying enzymatic activities to the use of the Pt nanomedicines, providing a paradigm shift in DNA damaging chemotherapy.
Cancer photothermal (PTT) and photodynamic therapies (PDT) have aroused tremendous attention with high spatial specificity, but they experience the challenges from the inefficient tumor accumulation and penetration of photosensitizers and dose-dependent side effects. Herein, persistent luminescence (PL)-activated nanomotors are developed with the integration of PL-illuminated PTT and PDT to overcome these limitations. PL nanodots of ZnGa 2 O 4 :Cr 3+ (ZGC) were deposited on mesoporous silica nanoparticles (NPs), followed by conjugation of silicon phthalocyanine as a photosensitizer and capping with polydopamine (PDA) to fabricate Janus [email protected] NPs. ZGC nanodots on NPs are activated by external illumination to generate PL as an internal light source to excite PDA and phthalocyanine for persistent productions of heat and reactive oxygen species (ROS), avoiding high heat stress and ROS levels in the conventional intermittent phototherapy. In addition, the persistent heat gradients around the Janus NPs create thermophoretic force to drive their motions and enhance their cellular uptake, and the PL-illuminated PDT continuously produces intracellular ROS to damage tumor cells. Light activation of [email protected] obviously promotes accumulation and deep penetration of NPs into tumors and produces mild thermal and ROS levels with well distribution across the tumors. The self-propelled tumor distribution and the combined PDT/PTT treatment led to full inhibition of tumor growth and significant extension of animal survival, and there is no systemic toxicity and function fluctuation of the major organs. Thus, this study demonstrates a concise strategy to generate PL-activated motion for deep penetration and produce PL-illuminated PDT/PTT for synergistic tumor treatment.
Rapid and highly sensitive quantitative analysis of chlorpromazine (CPZ) in human whole blood is of great importance for human health. Herein, we utilize the screen-printed carbon electrodes (SPCE) as the electrode substrates for growth of highly electroactive and antifouling nanocomposite materials consisting of vertically ordered mesoporous silica films (VMSF) and electrochemically reduced graphene oxide (ErGO) nanosheets. The preparation of such VMSF/ErGO/SPCE could be performed by using an electrochemical method in a few seconds and the operation is controllable. Inner ErGO layer converted from graphene oxide (GO) in the growth process of VMSF provides oxygen-containing groups and two-dimensional π-conjugated planar structure for stable fabrication of outer VMSF layer. Owing to the π-π enrichment and excellent electrocatalytic abilities of ErGO, electrostatic preconcentration and antifouling capacities of VMSF, and inherent disposable and miniaturized properties of SPCE, the proposed VMSF/ErGO/SPCE sensor could be applied for quantitative determination of CPZ in human whole blood with high accuracy and sensitivity, good stability, and low sample consumption.Keywords:vertically ordered mesoporous silica films;screen-printed carbon electrodes;electrochemically reduced graphene oxide;chlorpromazine;electrochemical sensors;human whole blood
Nanoproperties, such as size, charge, and rigidity, have been demonstrated to be crucial for nanovehicles to overcome numerous gastrointestinal obstacles. However, the facile approach of modifying the rigidity of nanovehicles remains scarce, limiting understanding of how rigidity impacts their oral delivery. Inspired by the fact that cellular phospholipid content regulates plasma membrane rigidity, the rigidity of self-nanoemulsifiying drug delivery system (SNEDDS) could be fine-tuned via phosphocholine content while their size and zeta potential remain unchanged, using insulin as a model drug. Notably, soft SNEDDS exerted longer gastrointestinal transit time, higher drug release rate, stronger gastrointestinal stability and relatively lower mucus permeation but superior epithelial transcytosis than their hard counterparts in a macropinocytosis-dependent manner. The rigidity-related enhanced transcytosis was attributed to improved endocytosis, lysosome escape capability and exocytosis. Rats with type 1 diabetes exhibited greater oral insulin absorption and blood glucose lowering effect with soft SNEDDS. This study demonstrated the regulatory role of phospholipids in nanovehicle rigidity, which could help develop mechanically optimized nanomedicines in the future.
Peptide immune checkpoint inhibitors in cancer immunotherapy have attracted great attention recently, but oral delivery of these peptides remains a huge challenge due to the harsh gastrointestinal environment, large molecular size, high hydrophilic, and poor transmembrane permeability. Here, for the first time, a fish oil-based microemulsion was developed for oral delivery of programmed death-1/programmed cell death-ligand 1 (PD-1/PD-L1) blocking model peptide, OPBP-1. The delivery system was characterized, in vitro and in vivo studies were conducted to evaluate its overall implication. As a result, this nutraceutical microemulsion was easily formed without the need of co-surfactants, and it appeared light yellow, transparent, good flowability with a particle size of 152 ± 0.73 nm, with a sustained drug release manner of 56.45 ± 0.36% over 24 h and a great stability within the harsh intestinal environment. It enhanced intestinal drug uptake and transportation over human intestinal epithelial Caco-2 cells, and drastically elevated the oral peptide bioavailability of 4.1-fold higher than that of OPBP-1 solution. Meanwhile, the mechanism of these dietary droplets permeated over the intestinal enterocytic membrane was found via clathrin and caveolae-mediated endocytic pathways. From the in vivo studies, the microemulsion facilitated the infiltration of CD8 + T lymphocytes in tumors, with increased interferon-γ (IFN-γ) secretion. Thus, it manifested a promising immune anti-tumor effect and significantly inhibited the growth of murine colonic carcinoma (CT26). Furthermore, it was found that the fish oil could induce ferroptosis in tumor cells and exhibited synergistic effect with OPBP-1 for cancer immunotherapy. In conclusion, this fish oil-based formulation demonstrated great potential for oral delivery of peptides with its natural property in reactive oxygen species (ROS)-related ferroptosis of tumor cells, which provides a great platform for functional green oral delivery system in cancer immunotherapy.
Determination of antipsychotics from biological samples is meaningful in the field of clinical and forensic medicine. Compared to blood, keratinized matrices such as hair and nails have attracted increasing attention in drug analysis for wider detection window. Nevertheless, the distribution and stability of antipsychotics in keratinized matrices are not clarified yet. Therefore, we developed a LC-MS/MS based method for simultaneous determination of 10 antipsychotics from blood, hair and nails, with high recovery (78.1–107.4%, 71.3–93.5% and 75.2–90.5%), low LOD (5–10 pg/mL, 5–10 pg/mg and 5 pg/mg) and high accuracy (96.0%−101.6%, 97.5%−102.5% and 97.6–101.7%). The method was applied to sets of blood, hair, and nail samples of 54 patients who received long-term therapy, and significant correlations between drug concentrations in blood and hair was found, while the correlation between nails and other matrices varied depending on the drug. Except for olanzapine , the concentrations of antipsychotics in segmental hair samples were consistent with drug exposure. Besides, the hair and nail samples of suspects in two forensic cases were analyzed and provided supporting evidence for the suspects’ psychiatric state. Our research offered a deeper understanding of keratinized matrix as stable and retrospective bio-samples for antipsychotics detection in forensic practice.
Cancer phototherapy indicates advantages in ease of manipulation, negligible drug resistance, and spatiotemporal control but is confronted with challenges in tumor cell accessibility and intermittent light excitation. Herein, we propose a strategy with persistent luminescence (PL)-excited photothermal therapy (PTT), concurrent thermophoresis-propelled motion, and PL-triggered NO release, where PL emission is chargeable by ultrasonication for readily applicable to deep tumors. Mechanoluminescent (ML) nanodots of SrAl2O4:Eu2+ (SAOE) and PL nanodots of ZnGa2O4:Cr3+ (ZGC) were deposited on mesoporous silicates to obtain mSZ nanoparticles (NPs), followed by partially coating with polydopamine (PDA) caps and loading NO donors to prepare Janus mSZ@PDA-NO NPs. The ML emission bands of SAOE nanodots overlap with the excitation band of ZGC, and the persistent near-infrared (NIR) emission could be repeatedly activated by ultrasonication. The PL emission acts as an internal NIR source to produce a thermophoretic force and NO gas propellers to drive the motion of Janus NPs. Compared with the commonly used intermittent NIR illumination at both 660 and 808 nm, the persistent motion of ultrasound-activated NPs enhances cellular uptake and long-lasting PTT and intracellular NO levels to combat tumor cells without the use of any chemotherapeutic drugs. The ultrasound-activated persistent motion promotes intratumoral accumulation and tumor distribution of PTT/NO therapeutics and exhibits significantly higher tumor growth inhibition, longer animal survival, and larger intratumoral NO levels than those who experience external NIR illumination. Thus, this study demonstrates a strategy to activate PL emissions and construct PL-excited nanomotors for phototherapy in deep tissues.
Acute liver injury (ALI) is one of the most important causes of liver failure, and there are no FDA-approved drugs that could therapy late-stage ALI. It has been shown in this study that HA-PEI, a molecule formed by covalently combining HA and PEI, can effectively treat advanced ALI. Through the CD44 receptor, HA-PEI could target the liver actively, with the highest liver-targeting effect confirmed at 1000 K. The underlying mechanism of protection of HA-PEI is by increasing oxygen content, reducing ROS, and maintaining mitochondrial membrane potential. HA-PEI also inhibits the secretion of inflammatory factors and blocks the migration of immune cells to the liver, protecting the hepatocytes not suffer from secondary damage. More importantly, for late-stage ALI, NAC, as the only FDA-approved drug, is completely ineffective, whereas HA-PEI has an excellent therapeutic effect. This work provides a new safe therapeutic agent for ALI, which has a bright application prospect.
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