Modulating Intracellular Dynamics for Optimized Intracellular Release and Transcytosis Equilibrium.

Active transcytosis-mediated nanomedicine transport presents considerable potential in overcoming diverse delivery barriers, thereby facilitating tumor accumulation and penetration. Nevertheless, the persistent challenge lies in achieving a nuanced equilibrium between intracellular interception for drug release and transcytosis for tumor penetration. In this study, a comprehensive exploration is conducted involving a series of polyglutamine-paclitaxel conjugates featuring distinct hydrophilic/hydrophobic ratios (HHR) and tertiary amine-oxide proportions (TP) (OPGA-PTX). The screening process, meticulously focused on delineating their subcellular distribution, transcytosis capability, and tumor penetration, unveils a particularly promising candidate denoted as OPPX, characterized by an HHR of 10:1 and a TP of 100%. OPPX, distinguished by its rapid cellular internalization through multiple endocytic pathways, selectively engages in trafficking to the Golgi apparatus for transcytosis to facilitate accumulation within and penetration throughout tumor tissues and simultaneously sorted to lysosomes for cathepsin B-activated drug release. This study not only identifies OPPX as an exemplary nanomedicine but also underscores the feasibility of modulating subcellular distribution to optimize the active transport capabilities and intracellular release mechanisms of nanomedicines, providing an alternative approach to designing efficient anticancer nanomedicines.

Current research status and development prospects of embolic microspheres containing biological macromolecules and others.

Transcatheter arterial embolization (TACE) has been used in the treatment of malignant tumors, sudden hemorrhage, uterine fibroids, and other diseases, and with advances in imaging techniques and devices, materials science, and drug release technology, more and more embolic agents that are drug-carrying, self-imaging, or have multiple functions are being developed. Microspheres provide safer and more effective therapeutic results as embolic agents, with their unique spherical appearance and good embolic properties. Embolic microspheres are the key to arterial embolization, blocking blood flow and nutrient supply to the tumor target. This review summarizes some of the currently published embolic microspheres, classifies embolic microspheres according to matrix, and summarizes the characteristics of the microsphere materials, the current status of research, directions, and the value of existing and potential applications. It provides a direction to promote the development of embolic microspheres towards multifunctionalization, and provides a reference to promote the research and application of embolic microspheres in the treatment of tumors.

Nanodrugs based on co-delivery strategies to combat cisplatin resistance.

Cisplatin (CDDP), as a broad-spectrum anticancer drug, is able to bind to DNA and inhibit cell division. Despite the widespread use of cisplatin since its discovery, cisplatin resistance developed during prolonged chemotherapy, similar to other small molecule chemotherapeutic agents, severely limits its clinical application. Cisplatin resistance in cancer cells is mainly caused by three reasons: DNA repair, decreased cisplatin uptake/increased efflux, and cisplatin inactivation. In earlier combination therapies, the emergence of multidrug resistance (MDR) in cancer cells prevented the achievement of the desired therapeutic effect even with the accurate combination of two chemotherapeutic drugs. Therefore, combination therapy using nanocarriers for co-delivery of drugs is considered to be ideal for alleviating cisplatin resistance and reducing cisplatin-related toxicity in cancer cells. This article provides an overview of the design of cisplatin nano-drugs used to combat cancer cell resistance, elucidates the mechanisms of action of cisplatin and the pathways through which cancer cells develop resistance, and finally discusses the design of drugs and related carriers that can synergistically reduce cancer resistance when combined with cisplatin.

Alkylated EDTA potentiates antibacterial photodynamic activity of protoporphyrin.

Antibiotic resistance has garnered significant attention due to the scarcity of new antibiotics in development. Protoporphyrin IX (PpIX)-mediated photodynamic therapy shows promise as a novel antibacterial strategy, serving as an alternative to antibiotics. However, the poor solubility of PpIX and its tendency to aggregate greatly hinder its photodynamic efficacy. In this study, we demonstrate that alkylated EDTA derivatives (aEDTA), particularly C14-EDTA, can enhance the solubility of PpIX by facilitating its dispersion in aqueous solutions. The combination of C14-EDTA and PpIX exhibits potent antibacterial activity against Staphylococcus aureus (S. aureus) when exposed to LED light irradiation. Furthermore, this combination effectively eradicates S. aureus biofilms, which are known to be strongly resistant to antibiotics, and demonstrates high therapeutic efficacy in an animal model of infected ulcers. Mechanistic studies reveal that C14-EDTA can disrupt PpIX crystallization, increase bacterial membrane permeability and sequester divalent cations, thereby improving the accumulation of PpIX in bacteria. This, in turn, enhances reactive oxygen species (ROS) production and the antibacterial photodynamic activity. Overall, this effective strategy holds great promise in combating antibiotic-resistant strains.

Neutrophil Extracellular Traps-Inhibiting and Fouling-Resistant Polysulfoxides Potently Prevent Postoperative Adhesion, Tumor Recurrence, and Metastasis.

Peritoneal metastasis (PM) is considered one of the most dreaded forms of cancer metastases for both patients and physicians. Aggressive cytoreductive surgery (CRS) is the primary treatment for peritoneal metastasis. Unfortunately, this intensive treatment frequently causes clinical complications, such as postoperative recurrence, metastasis, and adhesion formation. Emerging evidence suggests that neutrophil extracellular traps (NETs) released by inflammatory neutrophils contribute to these complications. Effective NET-targeting strategies thus show considerable potential in counteracting these complications but remain challenging. Here, one type of sulfoxide-containing homopolymer, PMeSEA, with potent fouling-resistant and NET-inhibiting capabilities, is synthesized and screened. Hydrating sulfoxide groups endow PMeSEA with superior nonfouling ability, significantly inhibiting protein/cell adhesion. Besides, the polysulfoxides can be selectively oxidized by ClO- which is required to stabilize the NETs rather than H2O2, and ClO- scavenging effectively inhibits NETs formation without disturbing redox homeostasis in tumor cells and quiescent neutrophils. As a result, PMeSEA potently prevents postoperative adhesions, significantly suppresses peritoneal metastasis, and shows synergetic antitumor activity with chemotherapeutic 5-Fluorouracil. Moreover, coupling CRS with PMeSEA potently inhibits CRS-induced tumor metastatic relapse and postoperative adhesions. Notably, PMeSEA exhibits low in vivo acute and subacute toxicities, implying significant potential for clinical postoperative adjuvant treatment.

A Selective-Tumor-Penetrating Strategy via Unidirectional Direct Transfer for Intravesical Therapy of Bladder Cancer.

A selective tumor-penetrating strategy generally exploits tumor-targeted ligands to modify drugs so that the conjugate preferentially enters tumors and subsequently undergoes transcellular transport to penetrate tumors. However, this process shields ligands from their corresponding targets on the cell surface, possibly inducing an off-target effect during drug penetration at the tumor-normal interface. Herein, we first describe a selective tumor-penetrating drug (R11-phalloidin conjugates) for intravesical therapy of bladder cancer. The intravesical conjugates rapidly translocated across the mucus layer, specifically bound to tumors, and infiltrated throughout the tumor via direct intercellular transfer. Notably, direct transfer from normal cells to tumor cells was unidirectional because the pathways required for direct transfer, termed F-actin-rich tunneling nanotubes, were more unidirectionally extended from normal cells to tumor cells. Moreover, the intravesical conjugates displayed strong anticancer activity and well-tolerated biosafety in murine orthotopic bladder tumor models. Our study demonstrated the potential of a selective tumor-penetrating conjugate for effective intravesical anticancer therapy.

Synthesis on NIR-II Multifunctional Imaging and Photothermal Therapy of a Novel Water-Soluble Molecule.

The synthesis of water-soluble symmetric molecules with donor-acceptor-donor (D-A-D) structure is reported. The compound is connected by π bridge with 2-bromofluorene external polyethylene glycol 2000 as the shielding unit, and donor component and pyrrolopyrrole (DPP) as the acceptor unit. The D-A-D double donor fluorescent molecule P2-DPP is obtained by coupling reaction. The absorption peak and emission peak of the fluorescent molecule P2-DPP are 600 and 1020 nm, respectively. It has potential excellent imaging characteristics. It does not need to use nanoparticles formed by the DSPE-MPEG amphiphilic block to form micelles. The quantum yield reaches 0.6% and the penetration depth can reach 10 mm. The chemical is capable of achieving liver and renal metabolism. It has a good application prospect in the photothermal therapy of mouse tumors and realizes the integration of biological diagnosis and treatment.

Short bridging and partial derivatization synergistically modified ß-cyclodextrin bonded chiral stationary phases for improved enantioseparation.

ß-Cyclodextrin (ß-CD) and its derivatives have been widely employed in the field of chiral separation, but they are still faced the limitation of low enantioselectivity and complex processes. Derivatization with functional molecules or preparation as bridging dimers are the two main modifications for ß-CD to obtain chiral recognition compounds. Herein, a partially derived bridged ß-CD (CPI-EBCD) bonded chiral stationary phases was prepared to improve enantioseparation. The chiral recognition moiety was synthesized by a bridged ß-cyclodextrin dimer using a short-chain bridging agent (ethylenediamine) and then modifying the bridged cyclodextrin with a 4-chlorophenylisocyanate (CPI) containing a benzene ring and polar group. Compared with natural ß-CD, dual-chambered CPI-EBCDs have better encapsulation synergies and more recognition sites with the guest molecule, while the short flexible bridging groups make the double cavities closer and more easily recognizable as linear molecules. The introduction of derived groups CPI provided more recognition sites and more types of interactions, including π-π interaction force, hydrogen bonding effect, and dipole-dipole interaction, thus improving the enantiomer-specific chirality recognition effect. The chiral stationary phase CPI-EBCDP was obtained by connecting CPI-EDCB with mesoporous silica microspheres by simple photochemical reaction using a green non-toxic diazo resin as coupling agent, simplifying preparation process. In the reversed phase mode of liquid chromatography, CPI-EBCDP has excellent chiral recognition ability, and 12 chiral compounds are successfully isolated by optimizing mobile phase conditions, with good reproducibility and stability. The successful preparation of this new chiral stationary phase provides an important reference for the subsequent development of cyclodextrin-like chiral stationary phases.

Peptide-based non-viral gene delivery: A comprehensive review of the advances and challenges.

Gene therapy is the most effective treatment option for diseases, but its effectiveness is affected by the choice and design of gene carriers. The genes themselves have to pass through multiple barriers in order to enter the cell and therefore require additional vectors to carry them inside the cell. In gene therapy, peptides have unique properties and potential as gene carriers, which can effectively deliver genes into specific cells or tissues, protect genes from degradation, improve gene transfection efficiency, and enhance gene targeting and biological responsiveness. This paper reviews the research progress of peptides and their derivatives in the field of gene delivery recently, describes the obstacles encountered by foreign materials to enter the interior of the cell, and introduces the following classes of functional peptides that can carry materials into the interior of the cell, and assist in transmembrane translocation of carriers, thus breaking through endosomal traps to enable successful entry of genetic materials into the nucleus of the cell. The paper also discusses the combined application of peptide vectors with other vectors to enhance its transfection ability, explores current challenges encountered by peptide vectors, and looks forward to future developments in the field.

Preparation of rare earth-doped nano-fluorescent materials in the second near-infrared region and their application in biological imaging.

Second near-infrared (NIR-II) fluorescence imaging (FLI) has gained widespread interest in the biomedical field because of its advantages of high sensitivity and high penetration depth. In particular, rare earth-doped nanoprobes (RENPs) have shown completely different physical and chemical properties from macroscopic substances owing to their unique size and structure. This paper reviews the synthesis methods and types of RENPs for NIR-II imaging, focusing on new methods to enhance the luminous intensity of RENPs and multi-band imaging and multi-mode imaging of RENPs in biological applications. This review also presents an overview of the challenges and future development prospects based on RENPs in NIR-II regional bioimaging.

Design of donor-acceptor conjugated polymers based on diketopyrrolopyrrole for NIR-II multifunctional imaging.

Diketopyrrolopyrrole (DPP) is an excellent photosensitizer and photothermal agent with the advantages of good planarity, strong electron affinity, high electron mobility, easy purification, easy structural modification and high molar absorption coefficient. It is regarded as one of the ideal choices for the design and synthesis of efficient organic photovoltaic materials. Therefore, two kinds of donor-acceptor (D-A) conjugated polymers were designed and synthesized with DPP as the acceptor, and their optical properties and applications in the near-infrared region were studied. The quantum yield (QY) of PBDT-DPP is 0.46%, and the highest temperature reached within 10 minutes after irradiation with a 660 nm laser is 60 °C. Another polymer, EDOT-DPP, has a QY of 0.48%, and its semiconductor polymer nanoparticle aqueous solution can reach 60 °C within 12 minutes under laser irradiation, achieving photothermal treatment of nude mice tumors. Both polymer NPs have good biocompatibility and promising applications in bioimaging and photothermal therapy.

Integrin-Targeted Theranostic Nanoparticles for Clinical MRI-Traceable Treatment of Liver Fibrosis.

Liver fibrosis is the critical stage in the development of chronic liver disease (CLD), from simple injury to irreversible cirrhosis. Timely detection and intervention of liver fibrosis are crucial for preventing CLD from progressing into a fatal condition. Herein, we developed iron oxide (Fe3O4) nanoparticles (IONPs) and ferulic acid (FA) coencapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), followed by surface modification with cRGD peptides (cRGD-PLGA/IOFA) for integrin-targeted clinical magnetic resonance imaging (MRI)-traceable treatment of liver fibrosis. The cRGD peptide linked on the surface of the PLGA/IOFA NPs could specifically bind to the overexpressed integrin αvß3 on activated hepatic stellate cells (HSCs) in the fibrotic liver, enabling the high-sensitive clinical MR imaging (3 T) and precise staging of liver fibrosis. The FA encapsulated in cRGD-PLGA/IOFA showed excellent efficacy in reducing oxidative stress and inhibiting the activation of HSCs through the transforming growth factor-ß (TGF-ß)/Smad pathway. Notably, the IONPs encapsulated in cRGD-PLGA/IOFA NPs could alleviate liver fibrosis by regulating hepatic macrophages through the NF-κB pathway, lowering the proportion of Ly6Chigh/CD86+, and degrading collagen fibers. The FA and IONPs in the cRGD-PLGA/IOFA produced a synergistic enhancement effect on collagen degradation, which was more effective than the IONPs treatment alone. This study demonstrates that cRGD-PLGA/IOFA NPs could effectively relieve liver fibrosis by acting on macrophages and HSCs and provide a new strategy for the clinical MRI-traceable treatment of liver fibrosis.

D-A-D organic fluorescent probes for NIR-II fluorescence imaging and efficient photothermal therapy of breast cancer.

Near-infrared second region (NIR-II) fluorescent probes are used in the diagnosis of early cancer due to their high tissue penetration. However, there are still few reports on organic small molecule fluorescent probes with NIR-II fluorescence imaging (NIR-II FI) combined with efficient photothermal therapy (PTT). In this study, planar cyclopentadithiophene (CPDT) was incorporated into the twisted structural skeleton (D-A-D), and the strong acceptor TTQ molecule (A) and the donor triphenylamine (D) were introduced to synthesize an organic small molecule (TCT) with enhanced NIR-II fluorescence emission performance. To improve the hydrophilicity of TCT molecules, we used the nanoprecipitation method to coat DSPE-mPEG2000 on the TCT molecules and obtained nanoparticles (TCT-NPs) with a strong absorption band, good water dispersibility, and NIR-II FI ability, which realized NIR-II FI-guided PTT for breast cancer tumors. Due to their effective near-infrared absorption, TCT-NPs exhibit high photothermal conversion efficiency (η = 40.1%) under 660 nm laser irradiation, making them a photothermal therapeutic agent with good performance. Therefore, TCT-NPs have the potential to diagnose, eliminate, and monitor the diffusion of cancer.

High-Throughput Screening of Surface Engineered Cyanine Nanodots for Active Transport of Therapeutic Antibodies into Solid Tumor.

The successful delivery of therapeutic biomacromolecules into solid tumor holds great challenge due to their high resistance to penetrate through the complex tumor microenvironments. Here, active-transporting nanoparticles are harnessed to efficiently deliver biomacromolecular drugs into solid tumors through cell transcytosis. A series of molecularly precise cyanine 5-cored polylysine G5 dendrimers (Cy5 nanodots) with different peripheral amino acids (G5-AA) is prepared. The capability of these positively charged nanodots to induce cell endocytosis, exocytosis, and transcytosis is evaluated via fluorescence-based high-throughput screen. The optimized nanodots (G5-R) are conjugated with αPD-L1 (a therapeutic monoclonal antibody binding to programmed-death ligand 1) (αPD-L1-G5-R) to demonstrate the nanoparticle-mediated tumor active transport. The αPD-L1-G5-R can greatly enhance the tumor-penetration capability through adsorption-mediated transcytosis (AMT). The effectiveness of αPD-L1-G5-R is tested in treating mice bearing partially resected CT26 tumors, mimicking the local immunotherapy of residual tumors post-surgery in clinic. The αPD-L1-G5-R embedded in fibrin gel can efficiently mediate tumor cell transcytosis, and deliver αPD-L1 throughout the tumor, thereby enhancing immune checkpoint blockade, reducing tumor recurrence, and significantly prolonging the survival time. The active-transporting nanodots are promising platforms for efficient tumor delivery of therapeutic biomacromolecules.

Preparation and application of hemostatic microspheres containing biological macromolecules and others.

Bleeding from uncontrollable wounds can be fatal, and the body's clotting mechanisms are unable to control bleeding in a timely and effective manner in emergencies such as battlefields and traffic accidents. For irregular and inaccessible wounds, hemostatic materials are needed to intervene to stop bleeding. Hemostatic microspheres are promising for hemostasis, as their unique structural features can promote coagulation. There is a wide choice of materials for the preparation of microspheres, and the modification of natural macromolecular materials such as chitosan to enhance the hemostatic properties and make up for the deficiencies of synthetic macromolecular materials makes the hemostatic microspheres multifunctional and expands the application fields of hemostatic microspheres. Here, we focus on the hemostatic mechanism of different materials and the preparation methods of microspheres, and introduce the modification methods, related properties and applications (in cancer therapy) for the structural characteristics of hemostatic microspheres. Finally, we discuss the future trends of hemostatic microspheres and research opportunities for developing the next generation of hemostatic microsphere materials.

Preparation and application of UPLC silica microsphere stationary phase:A review.

In this review, microspheres for ultra-performance liquid chromatography (UPLC) were reviewed in accordance with the literature in recent years. As people's demands for chromatography are becoming more and more sophisticated, the preparation and application of UPLC stationary phases have become the focus of researchers in this field. This new analytical separation science not only maintains the practicality and principle of high-performance liquid chromatography (HPLC), but also improves the step function of chromatographic performance. The review presents the morphology of four types of sub-2 µm silica microspheres that have been used in UPLC, including non-porous silica microspheres (NPSMs), mesoporous silica microspheres (MPSMs), hollow silica microspheres (HSMs) and core-shell silica microspheres (CSSMs). The preparation, pore control and modification methods of different microspheres are introduced in the review, and then the applications of UPLC in drug analysis and separation, environmental monitoring, and separation of macromolecular proteins was presented. Finally, a brief overview of the existing challenges in the preparation of sub-2 µm microspheres, which required further research and development, was given.

Engineered Extracellular Vesicles: A potential treatment for regeneration.

Extracellular vesicles (EVs) play a critical role in various physiological and pathological processes. EVs have gained recognition in regenerative medicine due to their biocompatibility and low immunogenicity. However, the practical application of EVs faces challenges such as limited targeting ability, low yield, and inadequate therapeutic effects. To overcome these limitations, engineered EVs have emerged. This review aims to comprehensively analyze the engineering methods utilized for modifying donor cells and EVs, with a focus on comparing the therapeutic potential between engineered and natural EVs. Additionally, it aims to investigate the specific cell effects that play a crucial role in promoting repair and regeneration, while also exploring the underlying mechanisms involved in the field of regenerative medicine.

Cell-Selective Binding Zwitterionic Polymeric Micelles Boost the Delivery Efficiency of Antibiotics.

Effective accumulation and penetration of antibiotics in the biofilm are critical issues for bacterial infection treatment. Red blood cells (RBCs) have been widely utilized to hitchhike nanocarriers for drug delivery. It is vital and challenging to find a nanocarrier with an appropriate affinity toward RBCs and bacteria for selective hitchhiking and release that determines the drug delivery efficiency and specificity. Herein, we report a zwitterionic polymer poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate) (OPDEA)-based micelle, which can hitchhike on RBCs in blood and preferentially release in the infection site. We found that OPDEA could bind to the RBCs cell membrane via phospholipid-related affinity and transfer to Gram-positive bacteria due to nearly an order of magnitude stronger interaction with the bacteria cell wall. The zwitterionic surface and cell-wall affinity of OPDEA-based micelles also promote their penetration in biofilm. The clarithromycin-loaded OPDEA micelles show efficient drug delivery into the infection site, resulting in excellent therapeutic performance in both peritonitis and pneumonia models by intravenous or spray administration. This simple RBC-selective hitchhiking and releasing antibiotic delivery system provides a promising strategy for the design of antibacterial nanomedicines.

Screening and investigation of a short antimicrobial peptide: AVGAV.

Bacterial resistance to various drugs is a major problem concerning the field of antibacterial agents. Fortunately, peptides with antibacterial activity can alleviate this problem. In this study, a short peptide (AVGAV) with excellent antibacterial activity was successfully screened from a peptide library by a self-made membrane chromatographic packing. The AVGAV peptide exhibits good biocompatibility and is non-toxic and non-irritating, which ensures that it presents safe antibacterial effects. AVGAV promoted wound healing in a mouse wound bacterial infection model. Most importantly, as a synthetic antimicrobial peptide, AVGAV can alleviate the problem of bacterial resistance, thus improving its application potential. This study provides a solution to the existing and potential problem of bacterial resistance.

Artificially reprogrammed stem cells deliver transcytosable nanocomplexes for improved spinal cord repair.

Stem cell transplantation holds great promise for restoring function after spinal cord injury (SCI), but its therapeutic efficacy heavily depends on the innate capabilities of the cells and the microenvironment at the lesion site. Herein, a potent cell therapeutic (NCs@SCs) is engineered by artificially reprogramming bone marrow mesenchymal stem cells (BMSCs) with oxidation-responsive transcytosable gene-delivery nanocomplexes (NCs), which endows cells with robust oxidative stress resistance and improved cytokine secretion. NCs@SCs can accumulate in the injured spinal cord after intravenous administration via chemotaxis and boost successive transcytosis to deliver NCs to neurons, augmenting ciliary neurotrophic factor (CNTF) production in both BMSCs and neurons in response to elevated ROS levels. Furthermore, NCs@SCs can actively sense and eliminate ROS and re-educate recruited M1-like macrophages into the anti-inflammatory M2 phenotype via a paracrine pathway, ultimately reshaping the inflammatory microenvironment. Synergistically, NCs@SCs exhibit durable survival and provide neuroprotection against secondary damage, enabling significant locomotor function recovery in SCI rats. Transcriptome analysis reveals that regulation of the ROS/MAPK signaling pathway is involved in SCI therapy by NCs@SCs. This study presents a nanomaterial-mediated cell-reprogramming approach for developing live cell therapeutics, showing significant potential in the treatment of SCI and other neuro-injury disorders.