Nuclear-Targeting Lipid PtIV Prodrug Amphiphile Cooperates with siRNA for Enhanced Cancer Immunochemotherapy by Amplifying Pt-DNA Adducts and Reducing Phosphatidylserine Exposure.

Patients treated with Pt-based anticancer drugs (PtII) often experience severe side effects and are susceptible to cancer recurrence due to the limited bioavailability of PtII and tumor-induced immunosuppression. The exposure of phosphatidylserine on the cell's outer surface induced by PtII results in profound immunosuppression through the binding of phosphatidylserine to its receptors on immune cells. Here, we report a novel approach for enhanced cancer chemoimmunotherapy, where a novel nuclear-targeting lipid PtIV prodrug amphiphile was used to deliver a small interfering RNA (siXkr8) to simultaneously amplify Pt-DNA adducts and reduce the level of exposure of phosphatidylserine. This drug delivery vehicle is engineered by integrating the PtIV prodrug with self-assembly performance and siXkr8 into a lipid nanoparticle, which shows tumor accumulation, cancer cell nucleus targeting, and activatable in a reduced microenvironment. It is demonstrated that nuclear-targeting lipid PtIV prodrug increases the DNA cross-linking, resulting in increased Pt-DNA adduct formation. The synergistic effects of the PtIV prodrug and siXkr8 contribute to the improvement of the tumor immune microenvironment. Consequently, the increased Pt-DNA adducts and immunogenicity effectively inhibit primary tumor growth and prevent tumor recurrence. These results underscore the potential of utilizing the nuclear-targeting lipid PtIV prodrug amphiphile to enhance Pt-DNA adduct formation and employing siXkr8 to alleviate immunosuppression during chemotherapy.

Programmed Cascade Polydopamine Nanoclusters for Pyroptosis-Based Tumor Immunotherapy.

Pyroptosis, an inflammatory cell death, plays a pivotal role in activating inflammatory response, reversing immunosuppression and enhancing anti-tumor immunity. However, challenges remain regarding how to induce pyroptosis efficiently and precisely in tumor cells to amplify anti-tumor immunotherapy. Herein, a pH-responsive polydopamine (PDA) nanocluster, perfluorocarbon (PFC)@octo-arginine (R8)-1-Hexadecylamine (He)-porphyrin (Por)@PDA-gambogic acid (GA)-cRGD (R-P@PDA-GC), is rationally design to augment phototherapy-induced pyroptosis and boost anti-tumor immunity through a two-input programmed cascade therapy. Briefly, oxygen doner PFC is encapsulated within R8 linked photosensitizer Por and He micelles as the core, followed by incorporation of GA and cRGD peptides modified PDA shell, yielding the ultimate R-P@PDA-GC nanoplatforms (NPs). The pH-responsive NPs effectively alleviate hypoxia by delivering oxygen via PFC and mitigate heat resistance in tumor cells through GA. Upon two-input programmed irradiation, R-P@PDA-GC NPs significantly enhance reactive oxygen species production within tumor cells, triggering pyroptosis via the Caspase-1/GSDMD pathway and releasing numerous inflammatory factors into the TME. This leads to the maturation of dendritic cells, robust infiltration of cytotoxic CD8+ T and NK cells, and diminution of immune suppressor Treg cells, thereby amplifying anti-tumor immunity.

Tailor-Made Autophagy Cascade Amplification Polymeric Nanoparticles for Enhanced Tumor Immunotherapy.

Chemotherapeutics can induce immunogenic cell death (ICD) by triggering autophagy and mediate antitumor immunotherapy. However, using chemotherapeutics alone can only cause mild cell-protective autophagy and be incapable of inducing sufficient ICD efficacy. The participation of autophagy inducer is competent to enhance autophagy, so the level of ICD is promoted and the effect of antitumor immunotherapy is highly increased. Herein, tailor-made autophagy cascade amplification polymeric nanoparticles STF@AHPPE are constructed to enhance tumor immunotherapy. Arginine (Arg), polyethyleneglycol-polycaprolactone, and epirubicin (EPI) are grafted onto hyaluronic acid (HA) via disulfide bond to form the AHPPE nanoparticles and autophagy inducer STF-62247 (STF) is loaded. When STF@AHPPE nanoparticles target to tumor tissues and efficiently enter into tumor cells with the help of HA and Arg, the high glutathione concentration leads to the cleavage of disulfide bond and the release of EPI and STF. Finally, STF@AHPPE induces violent cytotoxic autophagy and strong ICD efficacy. As compared to AHPPE nanoparticles, STF@AHPPE nanoparticles kill the most tumor cells and show the more obvious ICD efficacy and immune activation ability. This work provides a novel strategy for combining tumor chemo-immunotherapy with autophagy induction.

Co-Delivery of Doxorubicin and Anti-PD-L1 Peptide in Lipid/PLGA Nanocomplexes for the Chemo-Immunotherapy of Cancer.

The combined delivery of chemotherapeutics with checkpoint inhibitors of the PD-1/PD-L1 pathway provides a new approach for cancer treatment. Small-molecule peptide inhibitors possess short production cycle, low immunogenicity, and fewer side effects; however, their potential in cancer therapy is hampered by the rapid biodegradation and a nanocarrier is needed for efficient drug delivery. Herein, anticancer drug doxorubicin (DOX) and PD-L1 inhibitor peptide P-12 are co-loaded by a lipid polymer nanocomplex based on poly(lactic-co-glycolic acid) (PLGA) and DSPE-PEG. Octaarginine (R8)-conjugated DSPE-PEG renders the LPN efficient internalization by cancer cells. The optimal nanomedicine LPN-30-R82K@DP shows a diameter of 125 nm and a DOX and P-12 loading content of 5.0 and 6.2%, respectively. LPN-30-R82K@DP exhibits good physiological stability and enhanced cellular uptake by cancer cells. It successfully induces immunogenic cell death and PD-L1 blockade in CT26 cancer cells. The in vivo antitumor study further suggests that co-loaded nanomedicine efficiently suppresses CT26 tumor growth and elicits antitumor immune response. This study manifests that lipid polymer nanocomplexes are promising drug carriers for the efficient chemo-immunotherapy of cancer.

Smart Multistage "Trojan Horse"-Inspired Bovine Serum Albumin-Coated Liposomes for Enhancing Tumor Penetration and Antitumor Efficacy.

Poor antitumor drug penetration into tumor tissues is a global challenge in clinical cancer treatment. Here, we reported a smart multistage "Trojan Horse"-inspired bovine serum albumin (BSA)-coated liposome (HBM), including the mimics of capsid and secondary BSA-coated polymeric nanoparticles (NPs) for enhancing tumor penetration and antitumor efficacy. These drug-loaded polymeric NPs possess a capsid-like component, a well-distributed nanostructure (size: 190.1 ± 4.98 nm, PDI: 0.259), and an excellent drug loading content (15.85 ± 1.36%). Meaningfully, after the smart multistage BSA-coated liposome targeted the tumor tissue, the mimics of capsid were "taken off" under the condition of tumor-specific enzymes, releasing "Heart" BSA-modified secondary NPs to increase the ability to penetrate tumor cells for enhancing antitumor efficacy. As expected, the HBM efficiently achieves high drug penetration into PAN02 tumor cells. Moreover, compared to free DOX and HM (HBM without BSA) NPs, DOX/HBM NPs exhibited the strongest tumor penetration and the highest cytotoxicity against PAN02 tumor cells both in vitro (IC50 = 0.141 µg/mL) and in vivo. This smart multistage "Trojan Horse"-inspired BSA-coated liposome should provide a new hathpace for further development of polymeric NPs in clinical treatment.

Paravertebral Block versus Thoracic Epidural Analgesia for Postthoracotomy Pain Relief: A Meta-Analysis of Randomized Trials.

OBJECTIVE: Paravertebral block (PVB) and thoracic epidural analgesia (TEA) are commonly used for postthoracotomy pain management. The purpose of this research is to evaluate the effects of TEA versus PVB for postthoracotomy pain relief. METHODS: A systematic literature search was conducted in PubMed, EMBASE, Web of Science, and the Cochrane Library (last performed on August 2020) to identify randomized controlled trials comparing PVB and TEA for thoracotomy. The rest and dynamic visual analog scale (VAS) scores, rescue analgesic consumption, the incidences of side effects were pooled. RESULTS: Sixteen trials involving 1,000 patients were included in this meta-analysis. The pooled results showed that the rest and dynamic VAS at 12, 24, and rest VAS at 48 hours were similar between PVB and TEA groups. The rescue analgesic consumption (weighted mean differences: 3.81; 95% confidence interval [CI]: 0.982-6.638, p < 0.01) and the incidence of rescue analgesia (relative risk [RR]: 1.963; 95% CI: 1.336-2.884, p < 0.01) were less in TEA group. However, the incidence of hypotension (RR: 0.228; 95% CI: 0.137-0.380, p < 0.001), urinary retention (RR: 0.392; 95% CI: 0.198-0.776, p < 0.01), and vomiting (RR: 0.665; 95% CI: 0.451-0.981, p < 0.05) was less in PVB group. CONCLUSION: For thoracotomy, PVB may provide no superior analgesia compared with TEA but PVB can reduce side effects. Thus, individualized treatment is recommended. Further study is still necessary to determine which concentration of local anesthetics can be used for PVB and can provide equal analgesic efficiency to TEA.

Clinical characteristics, treatment and outcomes of acute postpartum inflammatory sacroiliitis: a retrospective study.

PURPOSE: We performed this research to report the clinical characteristics and clinical therapeutic strategies of acute postpartum inflammatory sacroiliitis. METHODS: We retrospectively analyzed the data of patients diagnosed with acute postpartum inflammatory sacroiliitis from 2014 to 2020. All their clinical details including clinical symptoms and signs, laboratory tests, radiologic examination, diagnosis and treatment process and clinical outcomes were obtained and analyzed in this retrospective analysis. RESULTS: Eleven patients diagnosed with acute postpartum inflammatory sacroiliitis complain of low back pain. Magnetic resonance imaging (MRI) is useful in diagnosing acute postpartum inflammatory sacroiliitis. The systemic non-steroidal anti-inflammatory drugs (NSAIDs) administration, sacroiliac joint injection, and physical therapy effectively alleviated the pain with symptoms disappearing, and the abnormal signal reduced in MRI. CONCLUSION: Acute postpartum inflammatory sacroiliitis is an uncommon disease with atypical symptoms. MRI examination may be the best diagnostic method. General NSAIDs and sacroiliac joint injections of local anesthetic plus corticosteroid under the guidance of fluoroscopy or ultrasound can achieve safe and effective treatment. This retrospective study was approved by the Committee on the Ethics of our hospital (No. 202101023). TRIAL REGISTRY: Trial registration was performed in the Chinese Clinical Trial Registry ( http://www.chictr.org.cn , No. ChiCTR2100045656).

The Programmed Cell Death Ligand-1/Programmed Cell Death-1 Pathway Mediates Pregnancy-Induced Analgesia via Regulating Spinal Inflammatory Cytokines.

BACKGROUND: The maternal pain threshold gradually increases during pregnancy, especially in late pregnancy. A series of mechanisms underlying pregnancy-induced analgesia have been reported. However, these mechanisms are still not completely clear, and the underlying molecular mechanisms need further investigation. We examined the relationship between the antinociceptive effect and the expression level of programmed cell death ligand-1 (PD-L1) during pregnancy and further observed the changes in pain thresholds and expression levels of cytokines in late-pregnant mice before and after blockade of PD-L1 or programmed cell death-1 (PD-1). METHODS: Part 1: Female mice were assigned to 3 groups (nonpregnant, late-pregnant, and postpartum). Part 2: Late-pregnant mice were assigned to 3 treatment groups (control [phosphate buffer solution], RMP1-14 [mouse anti-PD-1 antibody], and soluble PD-1 [sPD-1]). Behavioral testing (mechanical and thermal) and tissue (serum and spinal cord) analysis were performed on all groups. PD-L1, interleukin (IL)-10, tumor necrosis factor-α (TNF-α), and IL-6 expression levels in tissue were examined via reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and Western blot analysis. RESULTS: The mechanical and thermal pain thresholds were significantly increased in late pregnancy and decreased after delivery. PD-L1 expression was also elevated in late pregnancy and decreased after delivery. In addition, in the late stage of gestation, the maternal inflammatory microenvironment was dominated by anti-inflammatory factors. After administration of RMP1-14 or sPD-1, the pain thresholds of late-pregnant mice were significantly reduced. In late-pregnant mice, the high level of IL-10 was obviously reduced, and the low levels of TNF-α and IL-6 were elevated. CONCLUSIONS: The PD-L1/PD-1 pathway mediates pregnancy-induced analgesia, partially via the regulation of cytokines.

Tetrahedral DNA nanostructures for effective treatment of cancer: advances and prospects.

Recently, DNA nanostructures with vast application potential in the field of biomedicine, especially in drug delivery. Among these, tetrahedral DNA nanostructures (TDN) have attracted interest worldwide due to their high stability, excellent biocompatibility, and simplicity of modification. TDN could be synthesized easily and reproducibly to serve as carriers for, chemotherapeutic drugs, nucleic acid drugs and imaging probes. Therefore, their applications include, but are not restricted to, drug delivery, molecular diagnostics, and biological imaging. In this review, we summarize the methods of functional modification and application of TDN in cancer treatment. Also, we discuss the pressing questions that should be targeted to increase the applicability of TDN in the future.

microRNA-124 attenuates isoflurane-induced neurological deficits in neonatal rats via binding to EGR1.

Isoflurane anesthesia induces neuroapoptosis in the development of the brain. In this study, neonatal rats and hippocampal neurons were subjected to isoflurane exposure, in which the effect of miR-124 on the neurological deficits induced by isoflurane was evaluated. Isoflurane anesthesia models were induced in neonatal SD rats aged 7 days and then treated with miR-124 agomir, miR-124 antagomir, or LV-CMV-early growth response 1 (EGR1) plasmids. Then, the spatial learning and memory ability of rats were evaluated by Morris water maze. Furthermore, primary hippocampal neurons cultured 7 days were also exposed to isoflurane and transfected with miR-124 agomir, miR-124 antagomir, or LV-CMV-EGR1 plasmids. The targeting relationship of miR-124 and EGR1 was verified by the dual-luciferase reporter gene assay. To identify the effect of miR-124 on neuron activities, the viability and apoptosis of hippocampal neurons were assessed. In response to isoflurane exposure, miR-124 expression was reduced and EGR1 expression was increased in the hippocampal tissues and neurons. The isoflurane anesthesia damaged rats' spatial learning and memory ability, and reduced viability, and promoted apoptosis of hippocampal neurons. EGR1 was targeted and negatively regulated by miR-124. The treatment of miR-124 agomir improved rats' spatial learning and memory ability and notably increased hippocampal neuron viability and resistance to apoptosis, corresponding to an increased brain-derived neurotrophic factor (BDNF) expression, inhibited expression of proapoptotic factors (cleaved-Caspase-3 and Bax), and enhanced the expression of antiapoptotic factor (Bcl-2). Upregulated miR-124 inhibited the expression of EGR1, by which mechanism miR-124 reduced the neurological deficits induced by isoflurane in neonatal rats through inhibiting apoptosis of hippocampal neurons.

[Role of spinal P2X4 receptor in remifentanil-induced postoperative hyperalgesia].

OBJECTIVE: To explore the role of P2X4 receptor in opioid-induced hyperalgesia (OIH).
 Methods: A total of 30 Sprague-Dawley (SD) male rats were randomly divided into 5 groups: a saline (N0) group, a remifentanil at 0.5 µg/(kg.min) (R1) group, a remifentanil at 1.0 µg/(kg.min) (R2) group, a remifentanil at 1.5 µg/(kg.min) (R3) group, and a remifentanil at 5.0 µg/(kg.min) (R4) group. The paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured at follow time points to optimize the dosages: the day before treatment (T1), 30 min after tail intravenous catheterization (T2), and 30 min (T3), 1 h (T4), 2 h (T5), 24 h (T6) after withdrawal from remifentanil. Then, the rats were randomly divided into 2 groups: a saline group (N group), a remifentanil at 1.0 µg/(kg.min) group (R group). The PWMT and PWTL were measured at follow time points: T1, T2, and T4. The lumbar enlargement of spine was selected at 1 h after withdrawal from remifentanil, and the expression of P2X4 receptor mRNA and protein was examined in OIH. Additional male rats were selected and randomly divided into 2 groups: a plantar incision surgery followed by saline treatment group (I+N group), a plantar incision surgery followed by remifentanil treatment group (I+R group). The PWMT and PWTL were measured at follow time points: T1, T2, T3, T4, T5, T6, 48 h (T7) and 72 h (T8) after withdrawal from remifentanil. The lumbar enlargement of spine was selected at 1 h after withdrawal from remifentanil, the expression of P2X4 receptor mRNA and protein was examined by PCR and Western blotting, and the microglial activation in spine 1 h after withdrawal from remifentanil were assessed by immunofluorescence.
 Results: The pain thresholds including PWMT and PWTL in different groups were as follows: R4 group

IL-33/ST2 signaling contributes to radicular pain by modulating MAPK and NF-κB activation and inflammatory mediator expression in the spinal cord in rat models of noncompressive lumber disk herniation.

BACKGROUND: Immune and inflammatory responses occurring in the spinal cord play a pivotal role in the progression of radicular pain caused by intervertebral disk herniation. Interleukin-33 (IL-33) orchestrates inflammatory responses in a wide range of inflammatory and autoimmune disorders of the nervous system. Thus, the purpose of this study is to investigate the expression of IL-33 and its receptor ST2 in the dorsal spinal cord and to elucidate whether the inhibition of spinal IL-33 expression significantly attenuates pain-related behaviors in rat models of noncompressive lumbar disc herniation. METHODS: Lentiviral vectors encoding short hairpin RNAs that target IL-33 (LV-shIL-33) were constructed for gene silencing. Rat models of noncompressive lumber disk herniation were established, and the spines of rats were injected with LV-shIL-33 (5 or 10 µl) on the first day after the operation. Mechanical thresholds were evaluated during an observation period of 21 days. Moreover, the expression levels of spinal tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and cyclooxygenase 2 (COX-2) and the activation of the mitogen-activated protein kinases (MAPK) and nuclear factor-κB (NF-κB) pathways were evaluated to gain insight into the mechanisms related to the contribution of IL-33/ST2 signaling to radicular pain. RESULTS: The application of nucleus pulposus (NP) to the dorsal root ganglion (DRG) induced an increase in IL-33 and ST2 expression in the spinal cord, mainly in the dorsal horn neurons, astrocytes, and oligodendrocytes. Spinally delivered LV-shIL-33 knocked down the expression of IL-33 and markedly attenuated mechanical allodynia. In addition, spinal administration of LV-shIL-33 reduced the overexpression of spinal IL-1ß, TNF-α, and COX-2 and attenuated the activation of C-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and NF-κB/p65 but not p38. CONCLUSIONS: This study indicates that spinal IL-33/ST2 signaling plays an important role in the development and progression of radicular pain in rat models of noncompressive lumber disk herniation. Thus, the inhibition of spinal IL-33 expression may provide a potential treatment to manage radicular pain caused by intervertebral disk herniation.

[Role of DNA methyltransferases in the pathogenesis of neuropathic pain in rats].

OBJECTIVE: To explore the role of DNA methyltransferases (DNMTs) in the pathogenesis of neuropathic pain (NPP) in rats following sciatic nerve chronic constriction injury (CCI).
 METHODS: A total of 27 adult male Sprague-Dawley rats with successful implantation of lumbar intrathecal catheter were randomly divided into 3 groups: a sham + normal saline group (sham+NS group), a CCI+NS group, and a CCI+5-azacytidine group (CCI+5-AZA group) (n=9 in each group). The rats in the Sham+NS group and the CCI+NS group received NS, while the rats in the CCI+5-AZA group received 10 µmol/L of 5-AZA (a DNMTs inhibition) once a day through spinal injection from the 3th day to 14th day after CCI surgery. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) of ipsilateral hinds in the 3 groups were measured before or at the 3th, 5th, 7th, 10th or 14th day after CCI surgery. At the end of experiments, all rats were killed under deep anesthesia and their lumbar spinal cords were dissected to examine the DNMT1, DNMT3a and DNMT3b expression by RT-PCR, Western blot and immunohistochemistry, respectively.
 RESULTS: Compared with the sham+NS group, the MWT and TWL in the CCI+NS group were obviously reduced from the 3th day to the 14th day after surgery (both P<0.05). Compared with the CCI+NS group, the MWT and TWL in the CCI+5-AZA group were obviously increased from the 5th day to the 14th day after surgery (both P<0.05), but they were still reduced compared with the sham+NS group (both P<0.05). The DNMT1, DNMT3a and DNMT3b were highly expressed in the lumbar spinal dorsal horn in all rats, and the positive signals were mainly located in the nucleus. The DNMT1, DNMT3a and DNMT3b levels in the CCI+NS group were increased significantly compared with that in the sham+NS group on the 14th day after surgery (all P<0.05). The DNMT1, DNMT3a and DNMT3b expressions in the CCI+ 5-AZA group were decreased significantly compared with that in the CCI+NS group (all P<0.05), but they still increased compared with that in the sham+NS group (all P<0.05). 
 CONCLUSION: Up-regulation of DNMTs in the lumbar spinal may play an important role in the pathogenesis of NPP in CCI rats. DNMTs inhibitors (5-AZA) could reduce expression of DNMTs and attenuate CCI-induced NPP, which might be a potential therapeutic drug for NPP.

Parental Neuropathic Pain Influences Emotion-Related Behavior in Offspring Through Maternal Feeding Associated with DNA Methylation of Amygdale in Rats.

Chronic neuropathic pain has currently become a remarkable public health concern, considerably damaging not only the physiological but also the psychological aspects of humans. This study investigated whether neuropathic pain affects maternal care and assessed the effect of parental neuropathic pain on the development of neuropathic pain and emotion among offspring. Our results showed that mother rats suffered from chronic constriction injury (CCI) exhibited defective maternal care. The offspring fed by CCI mother rats (own or cross-fed) showed a significant increase in anxiety and anxiety-related behavior compared with that fed by sham-operated mother rats. The offspring fed by CCI mother rats also displayed decreased oxytocin expression in their supraoptic nucleus than that fed by sham-operated mother rats. Moreover, DNA methyltransferase (DNMT)1 expression in the amygdale was increased, whereas DNMT3a and DNMT3b expressions remained the same in offspring fed by CCI mother rats, as detected with immunohistochemistry and western blot analysis. In addition, the total DNA methylation in amygdale was upregulated in offspring fed by CCI mother rats. Considering the above findings, the data of this study suggest that parental neuropathic pain influences emotion-related behavior in offspring through maternal feeding behavior rather than through genetic factors and pregnancy experience that was associated with DNA methylation of amygdale in offspring.

A pH-sensitive imidazole grafted polymeric micelles nanoplatform based on ROS amplification for ferroptosis-enhanced chemodynamic therapy.

Highly toxic reactive oxygen species (ROS), crucial in inducing apoptosis and ferroptosis, are pivotal for cell death pathways in cancer therapy. However, the effectiveness of ROS-related tumor therapy is impeded by the limited intracellular ROS and substrates, coupled with the presence of abundant ROS scavengers like glutathione (GSH). In this research, we developed acid-responsive, iron-coordinated polymer nanoparticles (PPA/TF) encapsulating a mitochondrial-targeting drug alpha-tocopheryl succinate (α-TOS) for enhanced synergistic tumor treatment. The imidazole grafted micelles exhibit prolonged blood circulation and improve the delivery efficiency of the hydrophobic drug α-TOS. Additionally, PPA's design aids in delivering Fe3+, supplying ample iron ions for chemodynamic therapy (CDT) and ferroptosis through the attachment of imidazole groups to Fe3+. In the tumor's weakly acidic intracellular environment, PPA/TF facilitates pH-responsive drug release. α-TOS specifically targets mitochondria, generating ROS and replenishing those depleted by the Fenton reaction. Moreover, the presence of Fe3+ in PPA/TF amplifies ROS upregulation, promotes GSH depletion, and induces oxidative damage and ferroptosis, effectively inhibiting tumor growth. This research presents an innovative ROS-triggered amplification platform that optimizes CDT and ferroptosis for effective cancer treatment.

Nucleus-targeting Oxaplatin(IV) prodrug Amphiphile for enhanced chemotherapy and immunotherapy.

Platinum(II)-based drugs (PtII), which hinder DNA replication, are the most widely used chemotherapeutics. However, current PtII drugs often miss their DNA targets, leading to severe side effects and drug resistance. To overcome this challenge, we developed a oxaliplatin-based platinum(IV) (PtIV) prodrug amphiphile (C16-OPtIV-R8K), integrating a long-chain hydrophobic lipid and a nucleus-targeting hydrophilic peptide (R8K). This design allows the prodrug to self-assemble into highly uniform lipid nanoparticles (NTPtIV) for enhanced targeting chemotherapy and immunotherapy. Subsequently, NTPtIV's bioactivity and effects were examined at diverse levels, encompassing cancer cells, 3D tumor spheres, and in vivo. Our in vitro studies show a 74% cancer cell nucleus localization of platinum drugs-3.6 times higher than that of oxaliplatin, achieving more than a ten-fold increase in eliminating drug-resistant cancer cells. In vivo, NTPtIV shows efficient tumor accumulation, leading to suppressed tumor growth of murine breast cancer. Moreover, NTPtIV recruited more CD4+ and CD8+ T cells and reduced CD4+ Foxp3+ Tregs to synergistically enhance targeted chemotherapy and immunotherapy. Overall, this strategy presents a promising advancement in nucleus-targeted cancer therapy, synergistically boosting the efficacy of chemotherapy and immunotherapy.

Facile preparation of highly adhesive yet ultra-strong poly (vinyl alcohol)/cellulose nanocrystals composite hydrogel enabled by multiple networks structure.

Poly (vinyl alcohol) (PVA) hydrogel showed potential applications in bioengineering and wearable sensors fields. It is still a huge challenge to prepare highly adhesive yet strong poly (vinyl alcohol) hydrogel with good biocompatibility. Herein, we prepared a highly self-adhesive and strong poly (vinyl alcohol)/tannic acid@cellulose nanocrystals (PVA/TA@CNCs) composite hydrogel using TA@CNCs as functional nanofiller via facile freezing-thawing method. Multiple networks consisting of hydrogen bonding and coordination interactions endowed the hydrogel with high mechanical strength, excellent flexibility and fracture toughness with adequate energy dissipation mechanism and relatively dense network structure. The tensile strength of PVA/TA@CNCs hydrogel reached the maximum of 463 kPa, increasing by 367 % in comparison with pure PVA hydrogel (99 kPa), demonstrating the synergistic reinforcing and toughening effect of TA@CNCs. The hydrogel exhibited extremely high adhesion not only for various dry and wet substrates such as plastic, metal, Teflon, rubber, glass, leaf, but also sweaty human skin, showing good adhesion durability. The highest adhesion strength to silicone rubber, steel plate and pigskin could reach 197 kPa, 100 kPa and 46.9 kPa, respectively. Meanwhile the hydrogel had negligible cytotoxicity to cells and showed good biocompatibility.

Application of hydrogels for targeting cancer stem cells in cancer treatment.

Cancer stem cells (CSCs) are a major hindrance to clinical cancer treatment. Owing to their high tumorigenic and metastatic potential, CSCs are vital in malignant tumor initiation, growth, metastasis, and therapeutic resistance, leading to tumorigenesis and recurrence. Compared with normal tumor cells, CSCs express high levels of surface markers (CD44, CD90, CD133, etc.) and activate specific signaling pathways (Wnt/ß-catenin, Notch, and Hedgehog). Although Current drug delivery systems (DDS) precisely target CSCs, the heterogeneity and multidrug resistance of CSCs impede CSC isolation and screening. Conversely, hydrogel DDSs exhibit good biocompatibility and high drug delivery efficiency. Hydrogels are three-dimensional (3D) spatial structures for drug encapsulation that facilitate the controlled release of bioactive molecules. Hence, hydrogels can be loaded with drugs to precisely target CSCs. Their 3D structure can also culture non-CSCs and facilitate their transformation into CSCs. for identification and isolation. Given that their elastic modulus and stiffness characteristics reflect those of the cellular microenvironment, hydrogels can simulate extracellular matrix pathways and markers to regulate CSCs, disrupting the equilibrium between CSC and non-CSC transformation. This article reviews the CSC microenvironment, metabolism, signaling pathway, and surface markers. Additionally, we summarize the existing CSC targeting strategies and explore the application of hydrogels for CSC screening and treatment. Finally, we discuss potential advances in CSC research that may lead to curative measures for tumors through targeted and precise attacks on CSCs.

A Redox-Triggered Autophagy-Induced Nanoplatform with PD-L1 Inhibition for Enhancing Combined Chemo-Immunotherapy.

Epirubicin (EPI) alone can trigger mildly protective autophagy in residual tumor cells, resulting in an immunosuppressive microenvironment. This accelerates the recurrence of residual tumors and leads to antiprogrammed death ligand 1 (anti-PD-1)/PD-L1 therapy resistance, posing a significant clinical challenge in tumor immunotherapy. The combination of checkpoint inhibitors targeting the PD-1/PD-L1 pathway and amplifying autophagy presents an innovative approach to tumor treatment, which can prevent tumor immune escape and enhance therapeutic recognition. Herein, we aimed to synthesize a redox-triggered autophagy-induced nanoplatform with SA&EA-induced PD-L1 inhibition. The hyaluronic acid (HA) skeleton and arginine segment promoted active nanoplatform targeting, cell uptake, and penetration. The PLGLAG peptide was cleaved by overexpressing matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment, and the PD-L1 inhibitor D-PPA was released to inhibit tumor immune escape. The intense autophagy inducers, STF-62247 and EPI, were released owing to the cleavage of disulfide bonds influenced by the high glutathione (GSH) concentration in tumor cells. The combination of EPI and STF induced apoptosis and autophagic cell death, effectively eliminating a majority of tumor cells. This indicated that the SA&EA nanoplatform has better therapeutic efficacy than the single STF@AHMPP and EPI@AHMPTP groups. This research provided a way to set up a redox-triggered autophagy-induced nanoplatform with PD-L1 inhibition to enhance chemo-immunotherapy.

"Cicada Out of the Shell" Deep Penetration and Blockage of the HSP90 Pathway by ROS-Responsive Supramolecular Gels to Augment Trimodal Synergistic Therapy.

Deep penetration and downregulation of heat shock protein (HSP) expression in multimodal synergistic therapy are promising approaches for curing cancer in clinical trials. However, free small-molecule drugs and most drug vehicles have a low delivery efficiency deep into the tumor owing to poor drug penetration and hypoxic conditions at the tumor site. In this study, the objective is to use reactive oxygen species (ROS)-responsive supramolecular gels co-loaded with the photosensitizer Zn(II) phthalocyanine tetrasulfonic acid (ZnPCS4) and functionalized tetrahedral DNA (TGSAs) (G@P/TGSAs) to enhance deep tissue and cell penetration and block the HSP90 pathway for chemo- photodynamic therapy (PDT) - photothermal therapy (PTT) trimodal synergistic therapy. The (G@P/TGSAs) are injected in situ into the tumor to release ZnPCS4 and TGSAs under high ROS concentrations originating from both the tumor and PDT. TGSAs penetrate deeply into tumor tissues and augment photothermal therapy by inhibiting the HSP90 pathway. Proteomics show that HSP-related proteins and molecular chaperones are inhibited/activated, inhibiting the HSP90 pathway. Simultaneously, the TGSA-regulated apoptotic pathway is activated. In vivo study demonstrates efficient tumor penetration and excellent trimodal synergistic therapy (45% tumor growth inhibition).