Cytokines play an indispensable role in regulating various biological processes and have been verified as powerful therapeutic agents in cancer treatments after decades of development. However, their short half-lives in physiological environments and side effects impede their applications. To overcome these challenges, researchers have developed various delivery or expression systems to enhance the stability and tumor targeting of cytokines for ensuring their efficacy and safety in tumor therapy. In this review, we summarize the different carriers/vectors for optimizing cytokine delivery in various cancer treatments, including liposomes, hydrogels, cells, viruses, plasmids, etc. Additionally, the specific roles cytokines play in tumor treatments, the limitations of various platforms for cytokine delivery, and the future research directions of cytokine delivery systems are also introduced from different perspectives to provide new insights into the construction of cytokine-based anticancer drugs. Overall, cytokines are potent therapeutic agents that require the development of safer and more effective carriers/vectors to improve the effectiveness of tumor treatments. This review aims to deepen the understanding of the working mechanisms of cytokines used in cancer treatment and inspire the research in cytokine delivery systems to a greater extent.
Persistently activated signal transducer and activator of transcription 3 (STAT3) drives tumor malignancy and suppresses antitumor immunity, positioning it as an attractive immunotherapeutic target. Although numerous STAT3 inhibitors have been developed, their limited clinical success has motivated alternative strategies to restore the inactive state of STAT3 by blocking its phosphorylation. Here, we develop a Targeted Dephosphorylation NanoAdaptor (TDNA) that induces proximity between phosphorylated STAT3 (p-STAT3) and an endogenous phosphatase for targeted STAT3 dephosphorylation. Gold nanoclusters (GNCs) serve as a scaffold to conjugate STAT3-targeting peptides and protein tyrosine phosphatase non-receptor type 13 (PTPN13)-targeting peptides. Through precise optimization of the number and ratio of the two targeting peptides, TDNAs achieves more than 90% dephosphorylation of p-STAT3. In vivo studies further confirm that the TDNAs efficiently dephosphorylates p-STAT3 in tumor models within 24 h and activates antitumor immunity, thereby enhancing cancer immunotherapy. This study demonstrates the feasibility of inducing STAT3 dephosphorylation via proximity-based technology and provides a preclinical proof of concept for restoring STAT3 inactivity as a strategy for cancer immunotherapy.
Two-dimensional (2D) nanofluidic membranes have demonstrated extraordinary promise in high-throughput ionic transport systems for water-energy nexus applications. Nevertheless, the inability to engineer macroscopic, structurally ordered 2D membranes with precisely aligned nanochannels severely restricts their practical implementation. Here, we demonstrate a scalable shear-flow alignment strategy to assemble MXene/ANF composite membranes with vertically ordered nanochannels, which outperforms ionic flux leading to giant osmotic energy generation. The viscosity contrast between components generates sufficient shear-force gradients in dilute suspensions, enabling parallel alignment of MXene nanosheets during vacuum-assisted assembly. Under a 50-fold salinity gradient, the resulting vertically ordered architecture establishes ultralow-tortuosity ion highways, achieving unprecedented ionic flux (2.4 × 105 S/m2) with near-perfect cation selectivity (0.94), leading to a power density of 81.8 W m−2 under a 500-fold concentration gradient (5 M/0.01 M NaCl). Remarkably, the MXene/ANF nanocomposite simultaneously achieves exceptional mechanical robustness (tensile strength: 348.9 MPa, Young's modulus: 19.9 GPa) and environmental stability (97.5% performance retention after 30-day operation). Theoretical simulations demonstrate that highly aligned channels can significantly reduce resistance and energy loss during ion transmembrane process. The combination of flow-directed assembly and nanoscale interface engineering presented here provides new insights into scalable fabrication of high-performance ion exchange membranes for sustainable energy applications.
Wang and colleagues recently reported that lipid nanoparticle (LNP) administration promotes experimental pulmonary tumor metastasis through TLR9-MyD88- and cGASSTING-mediated neutrophil extracellular trap (NET) formation, invoking mitochondrial DNA (mtDNA) released from necrotic muscle cells as the activating ligand. This Opinion challenges a fundamental assumption underlying that interpretation: because TLR9 recognizes unmethylated CpG dinucleotides shared equally by mtDNA and bacterial DNA, and cGAS detects double-stranded DNA in a sequence-independent manner, the genetic rescue experiments are equally consistent with bacterial nucleic acid or lipopolysaccharide (LPS) contamination of the LNP preparations. Standard endotoxin detection methods, including the Limulus amebocyte lysate assay, are demonstrably unreliable in lipid matrices, where LPS lipid A inserts stably into hydrophobic domains and evades detection. Total lipid A quantification by EndoQuant (acid hydrolysis/HPLC-MS/MS), 16S rDNA analysis, polymyxin B pretreatment, and amplicon sequencing are required to resolve ligand identity. Until these controls are applied, the mtDNA hypothesis and a manufacturing contamination hypothesis remain equally supported by the available data — a distinction with profoundly different regulatory and clinical implications for LNP-based therapeutics.
