Biomimetic Nanoarchitectonics with Chitosan Nanogels for Collaborative Induction of Ferroptosis and Anticancer Immunity for Cancer Therapy.

Immunogenic cell death (ICD) shows promising therapeutic potential for tumor regression. However, the low sensitivity and immunosuppressive state of current cell death manners seriously impede tumor immunogenicity. Ferroptosis characterized by excessive lipid peroxidation, has emerged as a potential strategy to induce ICD and activate antitumor immune responses. However, the effectiveness of ferroptosis is limited by antioxidant regulatory networks, including the glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) pathways, presenting challenges for its induction. Herein, they propose a novel approach that involves utilizing functionalized chitosan-ferrocene-sodium alginate (CFA) crosslinked nanogels, which are modified to pravastatin (PRV) and M1 macrophage membrane (MM) (designing as CFA/PRV@MM). Specifically, ferrocene boots intracellular reactive oxygen species levels for efficient glutathione (GSH) depletion through Fenton reaction, thus disrupting the GPX4/GSH axis, while PRV intervenes in the mevalonate pathway to inhibit the FSP1/CoQ10 antioxidant axis, thereby synergistically causing pronounced ferroptotic damage and promoting ICD. The CFA/PRV@MM nanogels demonstrate superior therapeutic efficacy in a mouse breast model, resulting in effective tumor ablation and immune response with minimal side effects. RNA transcription analysis reveals that nanogels can significantly affect metabolic progress, as well as immune activation. This research provides valuable insights into the design of ferroptosis induction for cancer immunotherapy.

Tetrahydrobiopterin inhibitor-based antioxidant metabolic strategy for enhanced cancer ferroptosis-immunotherapy.

The induction of immunogenic ferroptosis in cancer cell is limited by the complex and delicate antioxidant system in the organism. Synergistic induction of oxidative damage and inhibition of the defensive redox system in tumor cells is critical to promote lethal accumulation of lipid peroxides and activate immunogenic death (ICD). To address this challenge, we present a multifunctional and dual-responsive layered double hydroxide (LDH) nanosheet to enhance immunogenic ferroptosis. The MTX-LDH@MnO2 nanoplatform is constructed by intercalating methotrexate (MTX) into LDH interlayers and electrostatically absorbing biomineralized ovalbumin (OVA)-MnO2 onto the LDH surface. Specifically, the released Mn2+ from the incorporated MnO2 triggers a Fenton-like reaction, leading to reactive oxygen species (ROS) accumulation, while the depletion of reduced glutathione (GSH) further intensifies oxidative stress, resulting in the induction of ferroptosis. MTX is released in response to the acidic environment of tumor cells and inhibits the regeneration of tetrahydrobiopterin (BH4), modulating the GTP cyclic hydrolase 1 (GCH1)/BH4 axis. MTX disrupts the antioxidant metabolic activity regulated by GCH1/BH4 axis and inhibits ROS consumption, further boosting the ferroptosis effect, which promoted the release of damage-associated molecular patterns (DAMPs) and triggered ICD in the tumor. This activation subsequently leads to significant antitumor immune reactions, including DCs maturation, infiltration of CD4+/CD8+ T cells and cytokines release. The redox-controllable nanoplatform demonstrates promising anticancer efficacy in a mouse breast model providing a novel strategy for cancer immunotherapy.

Boosting cancer immunotherapy by biomineralized nanovaccine with ferroptosis-inducing and photothermal properties.

Until now, treatment of refractory tumors and uncontrolled metastasis by cancer immunotherapy has not yet achieved satisfactory therapeutic results due to the insufficient in vivo immune response. Here, we proposed the construction of a therapeutic cancer nanovaccine Fe@OVA-IR820 with ferroptosis-inducing and photothermal properties for boosting cancer immunotherapy. Fe3+ ions were chelated inside the exogenous antigen ovalbumin (OVA) by biomineralization to form the nanovaccine, to which the photosensitizer IR820 was loaded by electrostatic incorporation. After intratumoral injection, in situ immunogenic cell death (ICD) was triggered as a result of Fe3+-dependent ferroptosis. Endogenous neoantigens and damage-associated molecular patterns (DAMPs) were released because of ICD and worked synergically with the exogenous OVA to provoke the immune response, which was further amplified by the photothermal effect after near-infrared irradiation. The enhanced recruitment and infiltration of T cells were observed and resulted in the suppression of the primary tumor. The therapeutic regiment that combined Fe@OVA-IR820 nanovaccine with cytotoxic T lymphocyte-associated protein 4 (CTLA-4) checkpoint blockade significantly boosted anti-cancer immunity and inhibited the growth of distal simulated metastases. Therefore, we proposed Fe@OVA-IR820 nanovaccine combined checkpoint blockade as a potential therapeutic strategy for melanoma treatment.

Metabolic Intervention Nanoparticles for Triple-Negative Breast Cancer Therapy via Overcoming FSP1-Mediated Ferroptosis Resistance.

Triple-negative breast cancer (TNBC) patients have a predisposition to poor prognosis due to the strong malignancy. Ferroptosis, a new form of cell death, is a candidate treatment for TNBC owing to its effectiveness in killing cancer cells. However, some TNBC cells exhibit an abnormal tumor metabolism, especially the ferroptosis suppressor protein 1 (FSP1)-mediated ubiquinone redox metabolism, which can promote ferroptosis resistance. Here, rosuvastatin (RSV) is encapsulated in silk fibroin (SF) nanoparticle (designated as Cu-SF(RSV) NPs) for TNBC inhibition by overcoming FSP1-mediated ferroptosis resistance. RSV intervenes in metabolic mevalonate pathway to disturb the redox homeostasis regulated by CoQ/FSP1 axis, thereby overcoming ferroptosis resistance. Besides, Cu-SF(RSV) NPs can generate reactive oxygen species and deplete glutathione to facilitate redox stress, thereby amplifying ferroptosis effect. Thus, it is anticipated that the metabolic intervention nanoparticles, Cu-SF(RSV) NPs, can be exploited as a promising therapeutic platform for clinical TNBC treatment.

Improved cancer phototheranostic efficacy of hydrophobic IR780 via parenteral route by association with tetrahedral nanostructured DNA.

As a photosensitizer with effective photothermal (PTT) and photodynamic (PDT) response, IR780 has been widely explored as promising cancer phototheranostic molecule. However, the systematic administration of IR780 usually suffers from poor water solubility and low photostability, so that it cannot be administrated by parenteral route. In this study, we design a tetrahedral DNA (Td)-based nanosystem to load IR780 (IR780@Td) via electrostatic interaction and π-π stacking. After encapsulation, the water solubility and photostability of IR780 have been greatly improved, and the IR780@Td shows an appropriate nanoformulated size (224 nm) to facilitate hyperthermia-mediated tumor targeting by EPR effect. The nanostructure of Td is proved to be crucial for the proper size and good stability of IR780@Td nanoformulation for in vivo application. The in vitro and ex vivo PTT/PDT efficiencies of IR780 are improved in IR780@Td group. In the tumor-bearing mice, the accumulation of IR780 in tumor site is significantly high in IR780@Td group. Under near-infrared laser irradiation, the intravenous administration of IR780@Td promotes the tumor imaging and enhances anti-tumor effect than IR780 treatment. In summary, the proposed strategy shows promising effect in facilitating intravenous injection of IR780 and enhancing the phototheranostic efficacy for cancer treatment.

Polygenic evidence and overlapped brain functional connectivities for the association between chronic pain and sleep disturbance.

Chronic pain and sleep disturbance are highly comorbid disorders, which leads to barriers to treatment and significant healthcare costs. Understanding the underlying genetic and neural mechanisms of the interplay between sleep disturbance and chronic pain is likely to lead to better treatment. In this study, we combined 1206 participants with phenotype data, resting-state functional magnetic resonance imaging (rfMRI) data and genotype data from the Human Connectome Project and two large sample size genome-wide association studies (GWASs) summary data from published studies to identify the genetic and neural bases for the association between pain and sleep disturbance. Pittsburgh sleep quality index (PSQI) score was used for sleep disturbance, pain intensity was measured by Pain Intensity Survey. The result showed chronic pain was significantly correlated with sleep disturbance (r = 0.171, p-value < 0.001). Their genetic correlation was rg = 0.598 using linkage disequilibrium (LD) score regression analysis. Polygenic score (PGS) association analysis showed PGS of chronic pain was significantly associated with sleep and vice versa. Nine shared functional connectivity (FCs) were identified involving prefrontal cortex, temporal cortex, precentral/postcentral cortex, anterior cingulate cortex, fusiform gyrus and hippocampus. All these FCs mediated the effect of sleep disturbance on pain and seven FCs mediated the effect of pain on sleep disturbance. The chronic pain PGS was positively associated with the FC between middle temporal gyrus and hippocampus, which further mediated the effect of chronic pain PGS on PSQI score. Mendelian randomization analysis implied a possible causal relationship from chronic pain to sleep disturbance was stronger than that of sleep disturbance to chronic pain. The results provided genetic and neural evidence for the association between pain and sleep disturbance, which may inform future treatment approaches for comorbid chronic pain states and sleep disturbance.

BAF45D knockdown decreases cell viability, inhibits colony formation, induces cell apoptosis and S-phase arrest in human pancreatic cancer cells.

Pancreatic cancer, an extremely aggressive malignancy, is resistant to chemo- or radiotherapy. The rapid progression of pancreatic cancer without distinctive clinical sign makes early diagnosing and/or treating very difficult. BAF45D, a member of the d4 domain family, is involved in oncogenic processes. However, the role of BAF45D in pancreatic tumorigenesis is largely unclear. Our goal is to examine BAF45D protein expression after lentivirus-mediated Baf45d RNAi and explore the effects of BAF45D knockdown on cell proliferation, cell apoptosis, and cell cycle of human pancreatic cancer cells. Here our results showed that Baf45d RNAi downregulated BAF45D protein levels and decreased cell viability, increased cell apoptosis, and decreased colony formation in BxPC-3 cells. Moreover, BAF45D knockdown induced S-phase arrest in BxPC-3 cells. Our results here suggest that BAF45D may play a crucial role in tumorigenic properties of human pancreatic cancer cells.

[Therapeutic efficacy of compound Xuanju capsule on type III prostatitis].

OBJECTIVE: To evaluate the therapeutic effect of Compound Xuanju Capsule on type III prostatitis. METHODS: A total of 242 patients with type III prostatitis diagnosed by the NIH criteria were randomly divided into an experimental and a control group of equal number, the former treated with Compound Xuanju Capsule + Tamsulosin Hydrochloride, and the latter with Quinolinone antibiotics + Tamsulosin and Hydrochloride, both for 6 months. After treatment, we assessed the therapeutic effects based on the NIH-CPSI scores and the improvement of relevant complications. RESULTS: All the 242 patients completed the treatment. The total effectiveness rate was 77.69% (94/121) in the experimental group, 71.56% (78/109) in those with complications. In comparison, it was only 47.10% (57/121) in the control group, 31.78% (34/107) in those with complications. Both the NIH-CPSI scores and the improvement of complications were significantly higher in the experimental than in the control group (P < 0.05). CONCLUSION: Compound Xuanju Capsule has a good therapeutic effect on type III prostatitis.

[Effect of targeted argon-helium cryoablation on the portal region in canine livers].

OBJECTIVE: To observe the effect of targeted argon-helium cryoablation on portal region of the liver in dogs by observing the pathological changes in the first-order branches of the Glisson ductal system. METHODS: Twelve healthy dogs underwent percutaneous targeted argon-helium cryoablation of the liver and sacrificed at 3 and 28 days after the cryoablation to observe the pathological changes in target area for cryoablation and the first-order branches of the Glisson ductal system. RESULTS: No obvious damage was not found in the vascular wall of the portal vein by gross or microscopic observation, but the liver tissue in the vicinity of the blood vessels showed total necrosis. In spite of the injuries of different degrees in the first-order bile duct system after argon-helium cryoablation, no severe damages such as perforation or full-thickness necrosis occurred in bile duct wall, and most of the injuries were temporary and reversible. The size of the ablated area on day 28 was significantly reduced as compared with that on day 3 following the cryoablation (P<0.05). In the acute stage after the cryoablation (1-3 days), ALT and AST levels increased significantly in (P<0.05) but recovered 1-4 weeks later (P>0.05). The cryoablated area was basically consistent with the pathological area that underwent necrosis (P>0.05). CONCLUSION: Targeted argon-helium cryoablation can cause total destruction of the liver tissue around the blood vessel without damaging the vascular walls of the portal vein. Argon-helium cryoablation induces relatively minor injuries to the bile duct of hepatic portal section and does not obviously damage the liver function, and the scope of tissue necrosis can be estimated according to the size of frozen area observed. Argon-helium cryoablation is a safe and minimally invasive operation with reliable therapeutic effect.