A Bioactive Injectable Hydrogel Regulates Tumor Metastasis and Wound Healing for Melanoma via NIR-Light Triggered Hyperthermia.

Surgical resection remains the mainstream treatment for malignant melanoma. However, challenges in wound healing and residual tumor metastasis pose significant hurdles, resulting in high recurrence rates in patients. Herein, a bioactive injectable hydrogel (BG-Mngel) formed by crosslinking sodium alginate (SA) with manganese-doped bioactive glass (BG-Mn) is developed as a versatile platform for anti-tumor immunotherapy and postoperative wound healing for melanoma. The incorporation of Mn2+ within bioactive glass (BG) can activate the cGAS-STING immune pathway to elicit robust immune response for cancer immunotherapy. Furthermore, doping Mn2+ in BG endows system with excellent photothermal properties, hence facilitating STING activation and reversing the tumor immune-suppressive microenvironment. BG exhibits favorable angiogenic capacity and tissue regenerative potential, and Mn2+ promotes cell migration in vitro. When combining BG-Mngel with anti-PD-1 antibody (α-PD-1) for the treatment of malignant melanoma, it shows enhanced anti-tumor immune response and long-term immune memory response. Remarkably, BG-Mngel can upregulate the expression of genes related to blood vessel formation and promote skin tissue regeneration when treating full-thickness wounds. Overall, BG-MnGel serves as an effective adjuvant therapy to regulate tumor metastasis and wound healing for malignant melanoma.

A Polyplatin with Hands-Holding Near-Infrared-II Fluorophores and Prodrugs at a Precise Ratio for Tracking Drug Fate with Realtime Readout and Treatment Feedback.

The in vivo fate of chemotherapeutic drugs plays a vital role in understanding the therapeutic outcome, side effects, and the mechanism. However, the lack of imaging abilities of drugs, tedious labeling processes, and premature leakage of imaging agents result in loss of fidelity between the drugs and imaging signals. Herein, an amphiphilic polymer is created by copolymerization of a near-infrared-II (NIR-II) fluorophore tracer (T) and an anticancer Pt(IV) prodrug (D) of cisplatin in a hand-holding manner into one polymer chain for the first time. The obtained PolyplatinDT is capable of delivering the drugs and the fluorophores concomitantly at a precise D/T ratio, thereby resulting in tracking the platinum drugs and even readout of them in real-time via NIR-II imaging. PolyplatinDT can self-assemble into nanoparticles, referred to as NanoplatinDT. Furthermore, a caspase-3 cleavable peptide that serves as an apoptosis reporter is attached to NanoplatinDT, resulting in NanoplatinDTR that are capable of simultaneously tracking platinum drugs and evaluating the therapeutic efficacy. Overall, it is reported here the design of the first theranostic polymer with anticancer drugs, drug tracers, and drug efficacy reporters that can work in concert to provide insight into the drug fate and mechanism of action.

Stimulus-Responsive Copper Complex Nanoparticles Induce Cuproptosis for Augmented Cancer Immunotherapy.

Cuproptosis, an emerging form of programmed cell death, has received tremendous attention in cancer therapy. However, the efficacy of cuproptosis remains limited by the poor delivery efficiency of copper ion carriers. Herein, copper complex nanoparticles (denoted as Cu(I) NP) are developed that can efficiently deliver copper complex into cancer cells to induce cuproptosis. Cu(I) NP demonstrate stimulus-responsive release of copper complexes, which results in mitochondrial dysfunction and promotes the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), leading to cuproptosis. Notably, Cu(I) NP not only induce cuproptosis, but also elicit robust immune responses to suppress tumor growth. Overall, this study provides a promising strategy for cuproptosis-based cancer therapy.

Organic-inorganic composite hydrogels: compositions, properties, and applications in regenerative medicine.

Hydrogels, formed from crosslinked hydrophilic macromolecules, provide a three-dimensional microenvironment that mimics the extracellular matrix. They served as scaffold materials in regenerative medicine with an ever-growing demand. However, hydrogels composed of only organic components may not fully meet the performance and functionalization requirements for various tissue defects. Composite hydrogels, containing inorganic components, have attracted tremendous attention due to their unique compositions and properties. Rigid inorganic particles, rods, fibers, etc., can form organic-inorganic composite hydrogels through physical interaction and chemical bonding with polymer chains, which can not only adjust strength and modulus, but also act as carriers of bioactive components, enhancing the properties and biological functions of the composite hydrogels. Notably, incorporating environmental or stimulus-responsive inorganic particles imparts smartness to hydrogels, hence providing a flexible diagnostic platform for in vitro cell culture and in vivo tissue regeneration. In this review, we discuss and compare a set of materials currently used for developing organic-inorganic composite hydrogels, including the modification strategies for organic and inorganic components and their unique contributions to regenerative medicine. Specific emphasis is placed on the interactions between the organic or inorganic components and the biological functions introduced by the inorganic components. The advantages of these composite hydrogels indicate their potential to offer adaptable and intelligent therapeutic solutions for diverse tissue repair demands within the realm of regenerative medicine.

Platinum Prodrug Nanoparticles with COX-2 Inhibition Amplify Pyroptosis for Enhanced Chemotherapy and Immune Activation of Pancreatic Cancer.

Pyroptosis, an emerging mechanism of programmed cell death, holds great potential to trigger a robust antitumor immune response. Platinum-based chemotherapeutic agents can induce pyroptosis via caspase-3 activation. However, these agents also enhance cyclooxygenase-2 (COX-2) expression in tumor tissues, leading to drug resistance and immune evasion in pancreatic cancer and significantly limiting the effectiveness of chemotherapy-induced pyroptosis. Here, an amphiphilic polymer (denoted as PHDT-Pt-In) containing both indomethacin (In, a COX-2 inhibitor) and platinum(IV) prodrug (Pt(IV)) is developed, which is responsive to glutathione (GSH). This polymer self-assemble into nanoparticles (denoted as Pt-In NP) that can disintegrate in cancer cells due to the GSH responsiveness, releasing In to inhibit the COX-2 expression, hence overcoming the chemoresistance and amplifying cisplatin-induced pyroptosis. In a pancreatic cancer mouse model, Pt-In NP significantly inhibit tumor growth and elicit both innate and adaptive immune responses. Moreover, when combined with anti-programmed death ligand (α-PD-L1) treatment, Pt-In NP demonstrate the ability to completely suppress metastatic tumors, transforming "cold tumors" into "hot tumors". Overall, the sustained release of Pt(IV) and In from Pt-In NP amplifies platinum-drug-induced pyroptosis to elicit long-term immune responses, hence presenting a generalizable strategy for pancreatic cancer.

The Influence of Envelope C-Terminus Amino Acid Composition on the Ratio of Cell-Free to Cell-Cell Transmission for Bovine Foamy Virus.

Foamy viruses (FVs) have extensive cell tropism in vitro, special replication features, and no clinical pathogenicity in naturally or experimentally infected animals, which distinguish them from orthoretroviruses. Among FVs, bovine foamy virus (BFV) has undetectable or extremely low levels of cell-free transmission in the supernatants of infected cells and mainly spreads by cell-to-cell transmission, which deters its use as a gene transfer vector. Here, using an in vitro virus evolution system, we successfully isolated high-titer cell-free BFV strains from the original cell-to-cell transmissible BFV3026 strain and further constructed an infectious cell-free BFV clone called pBS-BFV-Z1. Following sequence alignment with a cell-associated clone pBS-BFV-B, we identified a number of changes in the genome of pBS-BFV-Z1. Extensive mutagenesis analysis revealed that the C-terminus of envelope protein, especially the K898 residue, controls BFV cell-free transmission by enhancing cell-free virus entry but not the virus release capacity. Taken together, our data show the genetic determinants that regulate cell-to-cell and cell-free transmission of BFV.

Important role of N108 residue in binding of bovine foamy virus transactivator Tas to viral promoters.

BACKGROUND: Bovine foamy virus (BFV) encodes the transactivator BTas, which enhances viral gene transcription by binding to the long terminal repeat promoter and the internal promoter. In this study, we investigated the different replication capacities of two similar BFV full-length DNA clones, pBS-BFV-Y and pBS-BFV-B. RESULTS: Here, functional analysis of several chimeric clones revealed a major role for the C-terminal region of the viral genome in causing this difference. Furthermore, BTas-B, which is located in this C-terminal region, exhibited a 20-fold higher transactivation activity than BTas-Y. Sequence alignment showed that these two sequences differ only at amino acid 108, with BTas-B containing N108 and BTas-Y containing D108 at this position. Results of mutagenesis studies demonstrated that residue N108 is important for BTas binding to viral promoters. In addition, the N108D mutation in pBS-BFV-B reduced the viral replication capacity by about 1.5-fold. CONCLUSIONS: Our results suggest that residue N108 is important for BTas binding to BFV promoters and has a major role in BFV replication. These findings not only advances our understanding of the transactivation mechanism of BTas, but they also highlight the importance of certain sequence polymorphisms in modulating the replication capacity of isolated BFV clones.

Identification and functional characterization of Bet protein as a negative regulator of BFV3026 replication.

Foamy virus (FV) establishes persistent infection in the host without causing apparent disease. Besides the transactivator Tas protein, another auxiliary protein--Bet--has been reported in prototype foamy virus, equine foamy virus, and feline foamy virus. Here, we found the putative bbet gene in clone C74 from a cDNA library of bovine foamy virus strain 3026 (BFV3026) by comparison of gene localization, composition, and splicing features with other known bet genes. Subsequently, BBet protein was detected in BFV3026-infected cells by Western blot and immunofluorescence analyses. Analysis of the BBet mutant infectious clone (pBS-BFVdelBBet) revealed that BBet could inhibit BFV3026 replication. Consistent with this result, overexpression of BBet in Cf2Th cells reduced BFV replication by approximately threefold. Furthermore, virus replication levels similarly were reduced by approximately threefold in pBS-BFV-transfected and BFV3026-infected Cf2Th cells stably expressing BBet compared with control cells. After three passages, BFV3026 replicated more slowly in BBet-expressing cells. This study implicates BBet as a negative regulator of BFV replication and provides a resource for future studies on the function of this protein in the virus lifecycle.

Characterization of a full-length infectious clone of bovine foamy virus 3026.

The biological features of most foamy viruses (FVs) are poorly understood, including bovine foamy virus (BFV). BFV strain 3026 (BFV3026) was isolated from the peripheral blood mononuclear cells of an infected cow in Zhangjiakou, China. A full-length genomic clone of BFV3026 was obtained from BFV3026-infected cells, and it exhibited more than 99% amino acid (AA) homology to another BFV strain isolated in the USA. Upon transfection into fetal canine thymus cells, the full-length BFV3026 clone produced viral structural and auxiliary proteins, typical cytopathic effects, and virus particles. These results demonstrate that the full-length BFV3026 clone is fully infectious and can be used in further BFV3026 research.