Ultrathin Flexible Silica Nanosheets with Surface Chemistry-Modulated Affinity to Mammalian Cells.

Flexibility of nanomaterials is challenging but worthy to tune for biomedical applications. Biocompatible silica nanomaterials are under extensive exploration but are rarely observed to exhibit flexibility despite the polymeric nature. Herein, a facile one-step route is reported to ultrathin flexible silica nanosheets (NSs), whose low thickness and high diameter-to-thickness ratio enables folding. Thickness and diameter can be readily tuned to enable controlled flexibility. Mechanism study reveals that beyond the commonly used surfactant, the "uncommon" one bearing two hydrophobic tails play a guiding role in producing sheeted/layered/shelled structures, while addition of ethanol appropriately relieved the strong interfacial tension of the assembled surfactants, which will otherwise produce large curled sheeted structures. With these ultrathin NSs, it is further shown that the cellular preference for particle shape and rigidity is highly dependent on surface chemistry of nanoparticles: under high particle-cell affinity, NSs, and especially the flexible ones will be preferred by mammalian cells for internalization or attachment, while this preference is basically invalid when the affinity is low. Therefore, properties of the ultrathin silica NSs can be effectively expanded and empowered by surface chemistry to realize improved bio-sensing or drug delivery.

Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety.

Proteolysis Targeting Chimeras (PROTACs) represent a significant advancement in therapeutic drug development by leveraging the ubiquitin-proteasome system to enable targeted protein degradation, particularly impacting oncology. This review delves into the various types of PROTACs, such as peptide-based, nucleic acid-based, and small molecule PROTACs, each addressing distinct challenges in protein degradation. It also discusses innovative strategies like bridged PROTACs and conditional switch-activated PROTACs, offering precise targeting of previously "undruggable" proteins. The potential of PROTACs extends beyond oncology, with ongoing research and technological advancements needed to maximize their therapeutic potential. Future progress in this field relies on interdisciplinary collaboration and the integration of advanced computational tools to open new treatment avenues across various diseases.

The role of TNC in atherosclerosis and drug development opportunities.

Tenascin C (TNC), a rich glycoprotein of the extracellular matrix, exhibits a pro-atherosclerosis or anti-atherosclerosis effect depending on its location. TNC, especially its C domain/isoform (TNC-C), is strongly overexpressed in atherosclerotic plaque active areas but virtually undetectable in most normal adult tissues, suggesting that TNC is a promising delivery vector target for atherosclerosis-targeted drugs. Many delivery vectors were investigated by recognizing TNC-C, including G11, G11-iRGD, TN11, PL1, and PL3. F16 and FNLM were also investigated by recognizing TNC-A1 and TNC, respectively. Notably, iRGD was undergoing clinical trials. PL1 not only recognizes TNC-C but also the extra domain-B (EDB) of fibronectin (FN), which is also a promising delivery vector for atherosclerosis-targeted drugs, and several conjugate agents are undergoing clinical trials. The F16-conjugate agent F16IL2 is undergoing clinical trials. Therefore, G11-iRGD, PL1, and F16 have great development value. Furthermore, ATN-RNA and IMA950 were investigated in clinical trials as therapeutic drugs and vaccines by targeting TNC, respectively. Therefore, targeting TNC could greatly improve the success rate of atherosclerosis-targeted drugs and/or specific drug development. This review discussed the role of TNC in atherosclerosis, atherosclerosis-targeted drug delivery vectors, and agent development to provide knowledge for drug development targeting TNC.

The regulatory effect of growth differentiation factor 11 on different cells.

Growth differentiation factor 11 (GDF11) is one of the important factors in the pathophysiological process of animals. It is widely expressed in many tissues and organs of animals, showing its wide biological activity and potential application value. Previous research has demonstrated that GDF11 has a therapeutic effect on various diseases, such as anti-myocardial aging and anti-tumor. This has not only sparked intense interest and enthusiasm among academics but also spurred some for-profit businesses to attempt to develop GDF11 as a medication for regenerative medicine or anti-aging application. Currently, Sotatercept, a GDF11 antibody drug, is in the marketing application stage, and HS-235 and rGDF11 are in the preclinical research stage. Therefore, we believe that figuring out which cells GDF11 acts on and its current problems should be an important issue in the scientific and commercial communities. Only through extensive, comprehensive research and discussion can we better understand the role and potential of GDF11, while avoiding unnecessary risks and misinformation. In this review, we aimed to summarize the role of GDF11 in different cells and its current controversies and challenges, providing an important reference for us to deeply understand the function of GDF11 and formulate more effective treatment strategies in the future.

Camptothecin-based prodrug nanomedicines for cancer therapy.

Camptothecin (CPT) is a cytotoxic alkaloid that attenuates the replication of cancer cells via blocking DNA topoisomerase 1. Despite its encouraging and wide-spectrum antitumour activity, its application is significantly restricted owing to its instability, low solubility, significant toxicity, and acquired tumour cell resistance. This has resulted in the development of many CPT-based therapeutic agents, especially CPT-based nanomedicines, with improved pharmacokinetic and pharmacodynamic profiles. Specifically, smart CPT-based prodrug nanomedicines with stimuli-responsive release capacity have been extensively explored owing to the advantages such as high drug loading, improved stability, and decreased potential toxicity caused by the carrier materials in comparison with normal nanodrugs and traditional delivery systems. In this review, the potential strategies and applications of CPT-based nanoprodrugs for enhanced CPT delivery toward cancer cells are summarized. We appraise in detail the chemical structures and release mechanisms of these nanoprodrugs and guide materials chemists to develop more powerful nanomedicines that have real clinical therapeutic capacities.

Artificial Peroxisome hNiPt@Co-NC with Tetra-enzyme Activities for Colorimetric Glutathione Sensing.

Artificial peroxisome plays an important part in protocell system construction and disease therapy. However, it remains an enormous challenge to exploit a practicable artificial peroxisome with multiple and stable activities. Nanozymes with multienzyme mimetic activities stand out for artificial peroxisome preparation. Herein, a novel nanozyme─Co-nanoparticle-embedded N-enriched carbon nanocubes (Co,N-CNC) decorated by hollow NiPt nanospheres (hNiPt@Co-NC) with featured tetra-enzyme mimetic activities of natural peroxisome─was prepared. Due to the synergistic effect of hollow NiPt nanospheres (hNiPtNS) and cubic porous Co,N-CNC support, hNiPt@Co-NC exhibited oxidase (OXD), peroxidase (POD), catalase (CAT), and superoxide dismutase (SOD)-like activities with comparable catalytic efficiency, enabling it to be a competitive candidate for artificial peroxisome investigation. Based on the high OXD-mimetic activity of hNiPt@Co-NC, a facile colorimetric platform was proposed for reduced glutathione (GSH) detection with a wide linear range (0.1-5 µM, 5-100 µM) and a low detection limit (27 nM). Thus, the hNiPt@Co-NC with tetra-enzyme mimetic activities possessed bright prospects in diversified biotechnological applications, including artificial organelles, biosensing, and medical diagnostics.

Novel application potential of cinaciguat in the treatment of mixed hyperlipidemia through targeting PTL/NPC1L1 and alleviating intestinal microbiota dysbiosis and metabolic disorders.

Mixed hyperlipidemia, characterized by high levels of triglycerides and cholesterol, is a key risk factor leading to atherosclerosis and other cardiovascular diseases. Existing clinical drugs usually only work on a single indicator, decreasing either triglyceride or cholesterol levels. Developing dual-acting agents that reduce both triglycerides and cholesterol remains a great challenge. Pancreatic triglyceride lipase (PTL) and Niemann-Pick C1-like 1 (NPC1L1) have been identified as crucial proteins in the transport of triglycerides and cholesterol. Here, cinaciguat, a known agent used in the treatment of acute decompensated heart failure, was identified as a potent dual inhibitor targeting PTL and NPC1L1. We presented in vitro evidence from surface plasmon resonance analysis that cinaciguat interacted with PTL and NPC1L1. Furthermore, cinaciguat exhibited potent PTL-inhibition activity. Fluorescence-labeled cholesterol uptake analysis and confocal imaging showed that cinaciguat effectively inhibited cholesterol uptake. In vivo evaluation showed that cinaciguat significantly reduced the plasma levels of triglycerides and cholesterol, and effectively alleviated high-fat diet-induced intestinal microbiota dysbiosis and metabolic disorders. These results collectively suggest that cinaciguat has the potential to be further developed for the therapy of mixed hyperlipidemia.

Doxorubicin prodrug-based nanomedicines for the treatment of cancer.

The chemotherapeutic drug of doxorubicin (DOX) has witnessed widespread applications for treating various cancers. DOX-treated dying cells bear cellular modifications which allow enhanced presentation of tumor antigen and neighboring dendritic cell activation. Furthermore, DOX also facilitate the immune-mediated clearance of tumor cells. However, disadvantages such as severe off-target toxicity, and prominent hydrophobicity have resulted in unsatisfactory clinical therapeutic outcomes. The effective delivery of DOX drug molecules is still challenging despite the rapid advances in nanotechnology and biomaterials. Huge progress has been witnessed in DOX nanoprodrugs owing to their brilliant benefits such as tumor stimuli-responsive drug release capacity, high drug loading efficiency and so on. This review summarized recent progresses of DOX prodrug-based nanomedicines to provide deep insights into future development and inspire researchers to explore DOX nanoprodrugs with real clinical applications.

Hyaluronic acid-based prodrug nanomedicines for enhanced tumor targeting and therapy: A review.

Hyaluronic acid (HA) represents a natural polysaccharide which has attracted significant attention owing to its improved tumor targeting capacity, enzyme degradation capacity, and excellent biocompatibility. Its receptors, such as CD44, are overexpressed in diverse cancer cells and are closely related with tumor progress and metastasis. Accordingly, numerous researchers have designed various kinds of HA-based drug delivery platforms for CD44-mediated tumor targeting. Specifically, the HA-based nanoprodrugs possess distinct advantages such as good bioavailability, long circulation time, and controlled drug release and retention ability and have been extensively studied during the past years. In this review, the potential strategies and applications of HA-modified nanoprodrugs for drug molecule delivery in anti-tumor therapy are summarized.

Multifunctional small-molecule theranostic agents for tumor-specific imaging and targeted chemotherapy.

Cancer is one of the leading causes of death worldwide. Although great progress has been achieved in cancer diagnosis and treatment, novel therapies are still urgently needed to increase the efficacy and reduce the side effects of conventional therapies. Personalized medicine involves administering patients drugs that are specific to the characteristics of their tumors, and has significantly reduced side effects and increased overall survival rates. Multifunctional theranostic drugs are designed to combine diagnostic and therapeutic functions into a single molecule, which reduces the number of drugs administered to patients and increases patient compliance, and have shown great potential in propelling personalized medicine. This review focuses on multifunctional small-molecule theranostic agents for tumor-specific imaging and targeted chemotherapy, with a particular emphasis placed on highlighting design strategies and application in vitro or in vivo. The challenges and future perspectives of multifunctional small molecules are also discussed.

Photosensitizer-based small molecule theranostic agents for tumor-targeted monitoring and phototherapy.

Small molecule theranostic agents for tumor treatment exhibited triadic properties in tumor targeting, imaging, and therapy, which have attracted increasing attention as a potential complement for, or improved to, classical small molecule antitumor drugs. Photosensitizer have dual functions of imaging and phototherapy, and have been widely used in the construction of small molecule theranostic agents over the last decade. In this review, we summarized representative agents that have been studied in the field of small molecule theranostic agents based on photosensitizer in the last decade, and highlighted their characteristics and application in tumor-targeted monitoring and phototherapy. The challenges and future perspectives of photosensitizers in building small molecule theranostic agents for diagnosis and therapy of tumors were also discussed.

Intelligent delivery system targeting PD-1/PD-L1 pathway for cancer immunotherapy.

The drugs targeting the PD-1/PD-L1 pathway have gained abundant clinical applications for cancer immunotherapy. However, only a part of patients benefit from such immunotherapy. Thus, brilliant novel tactic to increase the response rate of patients is on the agenda. Nanocarriers, particularly the rationally designed intelligent delivery systems with controllable therapeutic agent release ability and improved tumor targeting capacity, are firmly recommended. In light of this, state-of-the-art nanocarriers that are responsive to tumor-specific microenvironments (internal stimuli, including tumor acidic microenvironment, high level of GSH and ROS, specifically upregulated enzymes) or external stimuli (e.g., light, ultrasound, radiation) and release the target immunomodulators at tumor sites feature the advantages of increased anti-tumor potency but decreased off-target toxicity. Given the fantastic past achievements and the rapid developments in this field, the future is promising. In this review, intelligent delivery platforms targeting the PD-1/PD-L1 axis are attentively appraised. Specifically, mechanisms of the action of these stimuli-responsive drug release platforms are summarized to raise some guidelines for prior PD-1/PD-L1-based nanocarrier designs. Finally, the conclusion and outlook in intelligent delivery system targeting PD-1/PD-L1 pathway for cancer immunotherapy are outlined.

Novel polyketide from Fusarium verticillioide G102 as NPC1L1 inhibitors.

One novel polyketide, fusaritide A (1), was isolated from a marine fish-derived halotolerant fungal strain Fusarium verticillioide G102. The structure was determined through extensive spectroscopic analysis and high-resolution electrospray ionization mass spectrometry. Fusaritide A (1) with unprecedented structure reduced cholesterol uptake by inhibiting Niemann-Pick C1-Like 1 (NPC1L1).

Research progress on antitumor activity of XRP44X and analogues as microtubule targeting agents.

Cancer threatens human health and life. Therefore, it is particularly important to develop safe and effective antitumor drugs. Microtubules, the main component of cytoskeleton, play an important role in maintaining cell morphology, mitosis, and signal transduction, which are one of important targets of antitumor drug research and development. Colchicine binding site inhibitors have dual effects of inhibiting proliferation and destroying blood vessels. In recent years, a series of inhibitors targeting this target have been studied and some progress has been made. XRP44X has a novel structure and overcomes some disadvantages of traditional inhibitors. It is also a multifunctional molecule that regulates not only the function of tubulin but also a variety of biological pathways. Therefore, the structure, synthesis, structure-activity relationship, and biological activity of XRP44X analogues reported in recent years were summarized in this paper, to provide a useful reference for the rational design of efficient colchicine binding site inhibitors.

Cytochalasans with Inhibitory Activity against NPC1L1 from the Endophytic Fungus Chaetomium nigricolor F5.

Mass spectrometry (MS)-based metabolic profiling of the endophytic fungus Chaetomium nigricolor F5 guided the isolation of five novel cytochalasans, chamisides B-F (1-5), and two known ones, chaetoconvosins C and D (6 and 7). Their structures including stereochemistry were unambiguously determined by MS, nuclear magnetic resonance, and single-crystal X-ray diffraction analyses. Compounds 1-3 share a new 5/6/5/5/7-fused pentacyclic skeleton in cytochalasans and are appropriately proposed to be the key biosynthetic precursors of co-isolated cytochalasans with a 6/6/5/7/5, 6/6/5/5/7, or 6/6/5 ring system. Remarkably, compound 5 with a relatively flexible side chain showed promising inhibition activity against the cholesterol transporter protein Niemann-Pick C1-like 1 (NPC1L1), expanding the function of cytochalasans.

Pleiotropic effects of a mitochondrion-targeted glutathione reductase inhibitor on restraining tumor cells.

Mitochondria has been identified as a target for tumor therapy. Agents preferentially concentrated in mitochondria may exert more potent antitumor effects by interfering with the normal function of mitochondria. Glutathione reductase (GR) in mitochondria is a crucial antioxidant enzyme to maintain mitochondrial function, and has been recognized as an important target for the development of anticancer drugs. Herein, we present a triphenylphosphonium-modified anticancer agent, MT-1, which can preferentially accumulate in mitochondria and bind to GR by covalent binding manner. As a result, morphology and function of mitochondria were severely damaged, as well as cellular energy supply was severely impeded due to the simultaneously inhibition against mitochondrial respiration and glycolysis. Moreover, MT-1 was found to bind to a completely new site of GR (C278) that has never considered as binding site of inhibitors before. This new binding mode led to the change of GR structure, which affected the stability of the transition state of the catalytic process, and finally led to the inhibition of GR activity. Thus, current study provided a potentially novel tumor therapeutic strategy by targeting novel sites of GR in mitochondrion.

Tetrazine bioorthogonal chemistry makes nanotechnology a powerful toolbox for biological applications.

Bioorthogonal chemistry enables researchers to manipulate bioactive molecules in living systems. These highly selective and biocompatible reactions can be carried out in various complex environments. Over the past two decades, a considerable number of strides have been made to expand the capacities of bioorthogonal chemistry coupled with the aim to fine-tune present reactions for specific applications. The good points of bioorthogonal chemistry have pushed material chemists to integrate bioorthogonal chemistry with nanotechnologies to broaden the biological applications of nanomaterials. Notably, bioorthogonal nanotechnologies fundamentally rely on, more than half, according to our investigation, tetrazine bioorthogonal chemistry (TBC) to function as bioorthogonal handles to react with target agents owing to the extremely rapid kinetics and high selectivities of TBC. Its utilization in combination with nanotechnologies has led to developments in various areas of biomedicine, such as in situ drug activation and targeted delivery, bioimaging and biosensing, and the understanding of cell-biomolecule interactions. Given the fantastic past achievements and the rapid developments in tetrazine bioorthogonal technologies, the future is certainly very bright.

The clinical development of antibody-drug conjugates for non-small cell lung cancer therapy.

Despite the emergence of molecular targeted therapy and immune checkpoint inhibitors as standard first-line treatments for non-small cell lung cancer (NSCLC), their efficacy in some patients is limited by intrinsic and acquired resistance. Antibody-drug conjugates (ADCs), a revolutionary class of antitumor drugs, have displayed promising clinical outcomes in cancer treatment. In 2022, trastuzumab deruxtecan (Enhertu) was approved for treating HER2-mutated NSCLC, thereby underscoring the clinical value of ADCs in NSCLC treatment strategies. An increasing number of ADCs, focusing on NSCLC, are undergoing clinical trials, potentially positioning them as future treatment options. In this review, we encapsulate recent advancements in the clinical research of novel ADCs for treating NSCLC. Subsequently, we discuss the mechanisms of action, clinical efficacy, and associated limitations of these ADCs.

Tetrazine bioorthogonal chemistry derived in vivo imaging.

Bioorthogonal chemistry represents plenty of highly efficient and biocompatible reactions that proceed selectively and rapidly in biological situations without unexpected side reactions towards miscellaneous endogenous functional groups. Arise from the strict demands of physiological reactions, bioorthogonal chemical reactions are natively selective transformations that are rarely found in biological environments. Bioorthogonal chemistry has long been applied to tracking and real-time imaging of biomolecules in their physiological environments. Thereinto, tetrazine bioorthogonal reactions are particularly important and have increasing applications in these fields owing to their unique properties of easily controlled fluorescence or radiation off-on mechanism, which greatly facilitate the tracking of real signals without been disturbed by background. In this mini review, tetrazine bioorthogonal chemistry for in vivo imaging applications will be attentively appraised to raise some guidelines for prior tetrazine bioorthogonal chemical studies.