Research progress on hydrogel-based drug therapy in melanoma immunotherapy.

Melanoma is one of the most aggressive skin tumors, and conventional treatment modalities are not effective in treating advanced melanoma. Although immunotherapy is an effective treatment for melanoma, it has disadvantages, such as a poor response rate and serious systemic immune-related toxic side effects. The main solution to this problem is the use of biological materials such as hydrogels to reduce these side effects and amplify the immune killing effect against tumor cells. Hydrogels have great advantages as local slow-release drug carriers, including the ability to deliver antitumor drugs directly to the tumor site, enhance the local drug concentration in tumor tissue, reduce systemic drug distribution and exhibit good degradability. Despite these advantages, there has been limited research on the application of hydrogels in melanoma treatment. Therefore, this article provides a comprehensive review of the potential application of hydrogels in melanoma immunotherapy. Hydrogels can serve as carriers for sustained drug delivery, enabling the targeted and localized delivery of drugs with minimal systemic side effects. This approach has the potential to improve the efficacy of immunotherapy for melanoma. Thus, the use of hydrogels as drug delivery vehicles for melanoma immunotherapy has great potential and warrants further exploration. [BMB Reports 2024; 57(2): 71-78].

Biomimetic Macrophage Membrane-Camouflaged Nanoparticles Induce Ferroptosis by Promoting Mitochondrial Damage in Glioblastoma.

The increasing understanding of ferroptosis has indicated its role and therapeutic potential in cancer; however, this knowledge has yet to be translated into effective therapies. Glioblastoma (GBM) patients face a bleak prognosis and encounter challenges due to the limited treatment options available. In this study, we conducted a genome-wide CRISPR-Cas9 screening in the presence of a ferroptosis inducer (RSL3) to identify the key driver genes involved in ferroptosis. We identified ALOX15, a key lipoxygenase (LOX), as an essential driver of ferroptosis. Small activating RNA (saRNA) was used to mediate the expression of ALOX15 promoted ferroptosis in GBM cells. We then coated saALOX15-loaded mesoporous polydopamine (MPDA) with Angiopep-2-modified macrophage membranes (MMs) to reduce the clearance by the mononuclear phagocyte system (MPS) and increase the ability of the complex to cross the blood-brain barrier (BBB) during specific targeted therapy of orthotopic GBM. These generated hybrid nanoparticles (NPs) induced ferroptosis by mediating mitochondrial dysfunction and rendering mitochondrial morphology abnormal. In vivo, the modified MM enabled the NPs to target GBM cells, exert a marked inhibitory effect on GBM progression, and promote GBM radiosensitivity. Our results reveal ALOX15 to be a promising therapeutic target in GBM and suggest a biomimetic strategy that depends on the biological properties of MMs to enhance the in vivo performance of NPs for treating GBM.

Engineered Extracellular Vesicle-Delivered CRISPR/Cas9 for Radiotherapy Sensitization of Glioblastoma.

Radiotherapy is a mainstay of glioblastoma (GBM) treatment; however, the development of therapeutic resistance has hampered the efficacy of radiotherapy, suggesting that additional treatment strategies are needed. Here, an in vivo loss-of-function genome-wide CRISPR screen was carried out in orthotopic tumors in mice subjected to radiation treatment to identify synthetic lethal genes associated with radiotherapy. Using functional screening and transcriptome analyses, glutathione synthetase (GSS) was found to be a potential regulator of radioresistance through ferroptosis. High GSS levels were closely related to poor prognosis and relapse in patients with glioma. Mechanistic studies demonstrated that GSS was associated with the suppression of radiotherapy-induced ferroptosis in glioma cells. The depletion of GSS resulted in the disruption of glutathione (GSH) synthesis, thereby causing the inactivation of GPX4 and iron accumulation, thus enhancing the induction of ferroptosis upon radiotherapy treatment. Moreover, to overcome the obstacles to broad therapeutic translation of CRISPR editing, we report a previously unidentified genome editing delivery system, in which Cas9 protein/sgRNA complex was loaded into Angiopep-2 (Ang) and the trans-activator of the transcription (TAT) peptide dual-modified extracellular vesicle (EV), which not only targeted the blood-brain barrier (BBB) and GBM but also permeated the BBB and penetrated the tumor. Our encapsulating EVs showed encouraging signs of GBM tissue targeting, which resulted in high GSS gene editing efficiency in GBM (up to 67.2%) with negligible off-target gene editing. These results demonstrate that a combination of unbiased genetic screens, and CRISPR-Cas9-based gene therapy is feasible for identifying potential synthetic lethal genes and, by extension, therapeutic targets.

Kill two birds with one stone: Engineered exosome-mediated delivery of cholesterol modified YY1-siRNA enhances chemoradiotherapy sensitivity of glioblastoma.

Glioblastoma (GBM) is the most malignant tumor of the central nervous system in adults. Irradiation (IR) and temozolomide (TMZ) play an extremely important role in the treatment of GBM. However, major impediments to effective treatment are postoperative tumor recurrence and acquired resistance to chemoradiotherapy. Our previous studies confirm that Yin Yang 1 (YY1) is highly expressed in GBM, whereby it is associated with cell dedifferentiation, survival, and therapeutic resistance. Targeted delivery of small interfering RNA (siRNA) without blood-brain barrier (BBB) restriction for eradication of GBM represents a promising approach for therapeutic interventions. In this study, we utilize the engineering technology to generate T7 peptide-decorated exosome (T7-exo). T7 is a peptide specifically binding to the transferrin receptor. T7-exo shows excellent packaging and protection of cholesterol-modified Cy3-siYY1 while quickly releasing payloads in a cytoplasmic reductive environment. The engineered exosomes T7-siYY1-exo could deliver more effciently to GBM cells both in vitro and in vivo. Notably, in vitro experiments demonstrate that T7-siYY1-exo can enhance chemoradiotherapy sensitivity and reverse therapeutic resistance. Moreover, T7-siYY1-exo and TMZ/IR exert synergistic anti-GBM effect and significantly improves the survival time of GBM bearing mice. Our findings indicate that T7-siYY1-exo may be a potential approach to reverse the chemoradiotherapy resistance in GBM.

Targeting radiation-tolerant persister cells as a strategy for inhibiting radioresistance and recurrence in glioblastoma.

BACKGROUND: Compelling evidence suggests that glioblastoma (GBM) recurrence results from the expansion of a subset of tumor cells with robust intrinsic or therapy-induced radioresistance. However, the mechanisms underlying GBM radioresistance and recurrence remain elusive. To overcome obstacles in radioresistance research, we present a novel preclinical model ideally suited for radiobiological studies. METHODS: With this model, we performed a screen and identified a radiation-tolerant persister (RTP) subpopulation. RNA sequencing was performed on RTP and parental cells to obtain mRNA and miRNA expression profiles. The regulatory mechanisms among NF-κB, YY1, miR-103a, XRCC3, and FGF2 were investigated by transcription factor activation profiling array analysis, chromatin immunoprecipitation, western blot analysis, luciferase reporter assays, and the MirTrap system. Transferrin-functionalized nanoparticles (Tf-NPs) were employed to improve blood-brain barrier permeability and RTP targeting. RESULTS: RTP cells drive radioresistance by preferentially activating DNA damage repair and promoting stemness. Mechanistic investigations showed that continual radiation activates the NF-κB signaling cascade and promotes nuclear translocation of p65, leading to enhanced expression of YY1, the transcription factor that directly suppresses miR-103a transcription. Restoring miR-103a expression under these conditions suppressed the FGF2-XRCC3 axis and decreased the radioresistance capability. Moreover, Tf-NPs improved radiosensitivity and provided a significant survival benefit. CONCLUSIONS: We suggest that the NF-κB-YY1-miR-103a regulatory axis is indispensable for the function of RTP cells in driving radioresistance and recurrence. Thus, our results identified a novel strategy for improving survival in patients with recurrent/refractory GBM.

LncRNA FTX promotes the malignant progression of colorectal cancer by regulating the miR-214-5p-JAG1 axis.

BACKGROUND: Long non-coding RNAs (lncRNAs) have recently been found to be vital regulators of various cancers, including colorectal cancer (CRC). It has been previously reported that the dysregulated expression of lncRNA Five prime to Xist (FTX) is involved in carcinogenesis. However, the role of lncRNA FTX in the progression of CRC is still unclear. METHODS: Fluorescence in situ hybridization (FISH) was used to detect the expression of lncRNA FTX and miR-214-5p in CRC tissues. Cell Counting Kit-8 assay, transwell assay, wound-healing assay, and proliferation assay were used to explore the function of lncRNA FTX in CRC cells. Quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and luciferase reporter assay were used to confirm the relationship between lncRNA FTX and miR-214-5p-jagged canonical Notch ligand 1 (JAG1). We further explored the role of lncRNA FTX in vivo using xenograft tumor assay. RESULTS: lncRNA FTX was found to be upregulated in CRC tissues by FISH. The downregulation of endogenous lncRNA FTX expression inhibited CRC cell proliferation, migration, and invasion. Mechanistically, lncRNA FTX sequestered miR-214-5p and thus released its repression on JAG1, driving the malignant progression of CRC. CONCLUSIONS: These findings give rise to a new perspective, the lncRNA FTX-miR-214-5p-JAG1 regulatory axis, in exploring the cancer-promoting mechanism of lncRNA FTX in CRC.

Coflex interspinous process dynamic stabilization for lumbar spinal stenosis: Long-term follow-up.

OBJECTIVE: To evaluate the long-term efficacy of Coflex dynamic stabilization device in the treatment of lumbar spinal stenosis. METHODS: The clinical and imaging data of 73 patients undergoing Coflex dynamic stabilization surgery from July 2008 to June 2012 were retrospectively analyzed. All patients had a minimum of 8 years of follow-up. Clinical data were used to assess the clinical efficacy, and radiographic parameters were measured for evaluation of ASD. RESULTS: 56 Patients were followed up for 107.6 ± 13.3 months. The visual analogue scale of pain (VAS), Owestry disability index (ODI) and Japanese Orthopedic Association Scores (JOA) improved significantly after surgery. At 6 months after surgery and the last follow-up, lumbar range of motion (ROM) was significantly lower than that before surgery (P < 0.001). ROM was slightly increased at the last follow-up compared with that 6 months after operation (P > 0.05). ROM of adjacent segments increased at 6 months and at the last follow-up compared with that before surgery (P > 0.05). At 6 months after surgery, intervertebral space height (ISH) and intervertebral foramen height (IFH) of implanted segment was significantly higher than that before surgery (P < 0.05). At the last follow-up, there was a decrease in ISH and IFH (P > 0.05). During the follow-up period, a total of 11 patients (19.6%) experienced complications and 6 patients (10.7%) underwent secondary surgery. CONCLUSION: Coflex interspinous process dynamic stabilization is effective in the long-term treatment of lumbar spinal stenosis, the ISH and IFH of implanted segment could be increased in a short period of time.