Efficient Therapy Strategies Research Articles

Enhancing melanoma therapy by modulating the immunosuppressive microenvironment with an MMP-2 sensitive and nHA/GNE co-encapsulated hydrogel

The immunosuppressive tumor microenvironment, such as lactic acid and matrix metalloproteinases (MMPs) overexpression, has been well confirmed to be adverse for tumor therapy. In current study, a tumor microenvironment modulatory hydrogel was successfully developed to treat melanoma by taking advantage of the synergistic effects of nano-hydroxyapatite (nHA) with well-documented selective anti-tumor action, lactate dehydrogenase A inhibitor (R)-GNE-140 (GNE), and matrix metalloproteinase-2 (MMP-2) sensitive peptide. The hydrogel was acquired by the reaction of 4-arm-polyethylene glycol-maleic anhydride (4-arm-PEG-MAL) and MMP-2 sensitive peptide (CC-14), in which nHA and GNE were co-encapsulated physically. The in vitro degradation tests confirmed the accelerated release of nHA and GNE from the hydrogel under less-acidic (pH 6.8) and MMP-2 containing conditions compared to those neutral or without MMP-2 conditions, demonstrating the pH and MMP-2 responsive properties of as-prepared hydrogel. Findings from in vitro cell experiments revealed that the hydrogel could stop the proliferation of melanoma cells by stacking cell cycle via lactic acid metabolic dysregulation and boosting cell apoptosis via nHA direct killing effect. Moreover, after hydrogel treatment, the rate of migration and aggressiveness of melanoma cells both reduced significantly. An in vivo anti-melanoma study showed that the hydrogel could inhibit tumor growth significantly and result in more CD8+ T cells and antigen-presenting cells but less Treg cells infiltration, ultimately leading to an enhanced therapeutic efficacy. As thus, the fabricated hydrogel demonstrated great promise for treating melanoma and could be a new potent strategy for efficient melanoma therapy. Statement of significanceNano-hydroxyapatite (nHA) has the capability of selectively killing cancer cells. The study reported a tumor microenvironment (TME) modulatory hydrogel with the goal of enhancing melanoma therapy efficacy by combining nHA administration with immunosuppressive microenvironment modulation. The hydrogel demonstrated pH and MMP-2 sensitivity. Hence, controlled release of nHA and lactate dehydrogenase A inhibitor (GNE) could be observed, and in situ MMP-2 consumption at the tumor site occurred. The hydrogel effectively inhibited the growth of melanoma cells. Furthermore, hydrogel increased the production of CD8+ T cells and antigen-presenting cells while decreasing the infiltration of Treg cells at the tumor site. This could transform the initial “cold” tumor into a “hot” tumor, ultimately resulting in an enhanced therapeutic effect.

Feracrylum—An Unexplored Aspect of Local Drug Delivery in Treating Chronic Periodontitis: An Original Research

ABSTRACT Background: Targeted and efficient therapy strategies are necessary to address the global threat that chronic periodontitis poses to oral health. Antibiotic resistance is one drawback of traditional methods like scaling and root planing in conjunction with systemic antibiotics. Techniques: A study with 120 people who had been diagnosed with chronic periodontitis was done using randomized controlled trials. The subjects were grouped as the Feracrylum group and the placebo group. Clinical measures were measured at baseline and again after 12 weeks. These parameters included gingival index, clinical attachment level, and “probing pocket depth (PD).” A 3% solution was locally applied to periodontal pockets in the Feracrylum group, whereas a saline solution was given to the placebo group. Findings: As compared with other cohorts, the Feracrylum group showed a substantial improvement in clinical attachment level and a significant decrease in PD (P < 0.05). Although not statistically significant, the gingival index reduction in the Feracrylum group showed a tendency in the direction of better gingival health. Conclusion: In summary, feracrylum has the potential as a localized medication delivery adjunct for chronic periodontitis, leading to positive clinical results. Larger sample numbers and longer follow-up times are required for future studies to confirm these results and maximize the use of feracrylum in periodontal treatment.

Effect of whole-body vibration on blood pressure in obese postmenopausal women. A randomized controlled study

Background. Menopause constitutes a natural biological process that reflects the end of the reproductive life of women and has been related to elevated risk factors for multiple strokes. Multiple studies have revealed that healthy women during menopause have increased abdominal obesity, triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), fasting blood glucose, body mass index (BMI), and blood pressure (BP) besides reduced high-density lipoprotein (HDL). Aim. We aim to determine the impact of whole body vibration (WBV) on BP and blood lipid profile in obese postmenopausal women. Subjects and methods. Our study enrolled 30 postmenopausal women with hypertension (HTN) who were aged 55–65 years old and had a BMI of 30–34.9 Kg/m2. An experienced physician diagnosed the participants with either pre-HTN or stage 1 HTN, with BP measurements of 140/90–159/99 mmHg. The participants were assigned into two equal groups (n = 15) in a random manner. Group A received a dietary regimen, whereas Group B received the dietary regimen along with a two-month whole body vibration (WBV) training program for 30 min, 3 sessions/week. Measurements were obtained for all participants, including their BP and serum TC, TG, HDL, and LDL levels pre- and post-therapy. Results. The results demonstrated that average systolic blood pressure (SBP), diastolic blood pressure (DBP), TC, TG, and LDL values significantly decreased in both groups, with a significant reduction favoring group B. Additionally, the average HDL value exhibited a statistically significant increase in both groups, with a significant increase favoring group B. Conclusion. WBV conjugated with a suitable nutritional intervention is considered a safe, user-friendly, and highly efficient physical therapy strategy for ameliorating blood lipid levels and lowering BP in postmenopausal women with HTN.

Epigallocatechin-3-gallate derived polymer coated Prussian blue for synergistic ROS elimination and antibacterial therapy

Reactive oxygen species (ROS) play a vital role in wound healing process by fighting against invaded bacteria. However, excess ROS at the wound sites lead to oxidative stress that can trigger deleterious effects, causing cell death, tissue damage and chronic inflammation. Therefore, we fabricated a core–shell structured nanomedicine with antibacterial and antioxidant properties via a facile and green strategy. Specifically, Prussian blue (PB) nanozyme was fabricated and followed by coating a layer of epigallocatechin-3-gallate (EGCG)-derived polymer via polyphenolic condensation reaction and self-assembly process, resulting in PB@EGCG. The introduction of PB core endowed EGCG-based polyphenol nanoparticles with excellent NIR-triggered photothermal properties. Besides, owing to multiple enzyme-mimic activity of PB and potent antioxidant capacity of EGCG-derived polymer, PB@EGCG exhibited a remarkable ROS-scavenging ability, mitigated intracellular ROS level and protected cells from oxidative damage. Under NIR irradiation (808 nm, 1.5 W/cm2), PB@EGCG (50 µg/mL) exerted synergistic EGCG-derived polymer-photothermal antibacterial activity against Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus).In vivo therapeutic effect was evaluated using a S. aureus-infected rat model indicated PB@EGCG with a prominent bactericidal ability could modulate the inflammatory microenvironment and accelerate wound healing. Overall, this dual-functional nanomedicine provides a promising strategy for efficient antibacterial therapy.

Mitochondria-Targeted Prodrug Nanoassemblies for Efficient Ferroptosis-Based Therapy via Devastating Ferroptosis Defense Systems.

Ferroptosis is a form of regulated cell death accompanied by lipid reactive oxygen species (ROS) accumulation in an iron-dependent manner. However, the efficiency of tumorous ferroptosis was seriously restricted by intracellular ferroptosis defense systems, the glutathione peroxidase 4 (GPX4) system, and the ubiquinol (CoQH2) system. Inspired by the crucial role of mitochondria in the ferroptosis process, we reported a prodrug nanoassembly capable of unleashing potent mitochondrial lipid peroxidation and ferroptotic cell death. Dihydroorotate dehydrogenase (DHODH) inhibitor (QA) was combined with triphenylphosphonium moiety through a disulfide-containing linker to engineer well-defined nanoassemblies (QSSP) within a single-molecular framework. After being trapped in cancer cells, the acidic condition provoked the structural disassembly of QSSP to liberate free prodrug molecules. The mitochondrial membrane-potential-driven accumulation of the lipophilic cation prodrug was delivered explicitly into the mitochondria. Afterward, the thiol-disulfide exchange would occur accompanied by downregulation of reduced glutathione levels, thus resulting in mitochondria-localized GPX4 inactivation for ferroptosis. Simultaneously, the released QA from the hydrolysis reaction of the adjacent ester bond could further devastate mitochondrial defense and evoke robust ferroptosis via the DHODH-CoQH2 system. This subcellular targeted nanoassembly provides a reference for designing ferroptosis-based strategy for efficient cancer therapy through interfering antiferroptosis systems.

CRISPRals: A Web Database for Assessing the CRISPR Defense System in the Ralstonia solanacearum Species Complex to Avoid Phage Resistance.

Clustered regularly interspaced short palindromic repeats (CRISPR) has been widely characterized as a defense system against phages and other invading elements in bacteria and archaea. A low percentage of Ralstonia solanacearum species complex (RSSC) strains possess the CRISPR array and the CRISPR-associated proteins (Cas) that would confer immunity against various phages. To provide a wide-range screen of the CRISPR presence in the RSSC, we analyzed 378 genomes of RSSC strains to find the CRISPR locus. We found that 20.1, 14.3, and 54.5% of the R. solanacearum, R. pseudosolanacearum, and R. syzygii strains, respectively, possess the CRISPR locus. In addition, we performed further analysis to identify the respective phages that are restricted by the CRISPR arrays. We found 252 different phages infecting different strains of the RSSC, by means of the identification of similarities between the protospacers in phages and spacers in bacteria. We compiled this information in a database with web access called CRISPRals (https://crisprals.yachaytech.edu.ec/). Additionally, we made available a number of tools to detect and identify CRISPR array and Cas genes in genomic sequences that could be uploaded by users. Finally, a matching tool to relate bacteria spacer with phage protospacer sequences is available. CRISPRals is a valuable resource for the scientific community that contributes to the study of bacteria-phage interaction and a starting point that will help to design efficient phage therapy strategies.

Synthesis of iron-boride/carbon-nitride composites and their applications in chemodynamic therapy

Chemodynamic therapy (CDT) is an emerging treatment strategy that inhibits tumor growth by catalyzing the generation of reactive oxygen species (ROS), such as hydroxyl radicals (•OH), using specific nanomaterials. Herein, we have developed a new class of iron-based nanomaterials, i.e., iron-based borides (FeB), using the superchaotropic effect of a boron cluster (closo-[B12H12]2–) and organic ligands, followed by high-temperature calcination. Experimental data and theoretical calculations revealed that FeB nanoparticles exhibit a Fenton-like effect, efficiently decomposing hydrogen peroxide into •OH and thus increasing the concentration of ROS. FeB nanomaterials demonstrate excellent catalytic performance, efficiently generate ROS, and exert significant antitumor effects in cell experiments and animal models. Therefore, FeB nanomaterials have considerable potential for application in tumor treatment and offer new insights for the development of novel and efficient cancer therapy strategies.

Stimuli-responsive nanoparticles delivered by a nasal-brain pathway alleviate depression-like behavior through extensively scavenging ROS.

Depression is one of the most common mental diseases, which seriously affects patients' physical and mental health. Emerging evidence has indicated that oxidative stress (OS) is a major cause of neurodegeneration involved in the pathogenesis of depression. Consequently, targeted reactive oxygen species (ROS) elimination is regarded as a promising strategy for efficient depression therapy. In addition, insufficient brain drug delivery is the main obstacle to depression therapy owing to the presence of the blood-brain barrier (BBB). To achieve the goals of bypassing the BBB and promoting antioxidant therapy for depression, a broad-spectrum ROS scavenging NPs was rationally designed through a nasal-brain pathway developed for combined ROS scavenging and brain drug delivery. A hexa-arginine (R6) modified ROS-responsive dextran (DEX) derivate was synthesized for antidepressant olanzapine (Olz) and H2 donor amino borane (AB) loading to prepare Olz/RDPA nanoparticles (NPs). Subsequently, the NPs were dispersed into a thermoresponsive hydrogel system based on poloxamer. In vitro and in vivo results demonstrated that Olz/RDPA in situ thermoresponsive hydrogel system could effectively deliver NPs to the brain via the nasal-brain pathway and alleviate depression-like behaviors through combined ROS depletion and inhibition of 5-HT dysfunction of the oxidative stress-induced. The proposed ROS-scavenging nanotherapeutic would open a new window for depression treatment. STATEMENT OF SIGNIFICANCE: ROS is an innovative therapeutic target involving the pathology of depression whereas targeted delivery of ROS scavenging has not been achieved yet. In the current study, ROS-responsive nanoparticles (Olz/RDPA NPs) were prepared and dispersed in a thermosensitive hydrogel for delivery through the nasal-brain pathway for the treatment of depression. Sufficient ROS depletion and improvement of delivery capacity by the nasal-brain pathway effectively could reverse oxidative stress and alleviate depressive-like behavior. Collectively, these nanoparticles may represent a promising strategy for the treatment of depression.

Biomimetic Prussian blue nanocomplexes for chemo-photothermal treatment of triple-negative breast cancer by enhancing ICD

Drug-induced immunogenic cell death (ICD) can efficiently inhibit tumor growth and recurrence through the release of tumor-associated antigens which activate both local and systemic immune responses. Pyroptosis has emerged as an effective means for inducing ICD; however, the development of novel pyroptosis inducers to specifically target tumor cells remains a pressing requirement. Herein, we report that Cinobufagin (CS-1), a main ingredient of Chansu, can effectively induce pyroptosis of triple-negative breast cancer (TNBC) cells, making it a potential therapeutic agent for this kind of tumor. However, the application of CS-1 in vivo is extremely limited by the high dosage/long-term usage and non-selectivity caused by systemic toxicity. To address these drawbacks, we developed a new nanomedicine by loading CS-1 into Prussian blue nanoparticles (PB NPs). The nanomedicine can release CS-1 in a photothermal-controlled manner inherited in PB NPs. Furthermore, hybrid membrane (HM) camouflage was adopted to improve the immune escape and tumor-targeting ability of this nanomedicine, as well. In vitro assays demonstrated that the chemo-photothermal combination treatment produced high-level ICD, ultimately fostering the maturation of dendritic cells (DCs). In vivo anti-tumor assessments further indicated that this strategy not only efficiently inhibited primary growth of MDA-MB-231 cells and 4T1 cells-bearing models but also efficiently attenuated distant tumor growth in 4T1 xenograft model. This was mechanistically achieved throuh the promotion of DCs maturation, infiltration of cytotoxic T lymphocyte into the tumor, and the inhibition of Treg cells. In summary, this work provides a novel strategy for efficient TNBC therapy by using nanomaterials-based multimodal nanomedicine through rational design.

A Biomimetic Adhesive and Robust Janus Patch with Anti-Oxidative, Anti-Inflammatory, and Anti-Bacterial Activities for Tendon Repair.

Early stage oxidative stress, inflammatory response, and infection after tendon surgery are highly associated with the subsequent peritendinous adhesion formation, which may diminish the quality and function of the repaired tendon. Although various anti-inflammatory and/or antibacterial grafts have been proposed to turn the scale, most of them suffer from the uncertainty of drug-induced adverse effects, low mechanical strength, and tissue adhesiveness. Here, inspired by the tendon anatomy and pathophysiology of adhesion development, an adhesive and robust dual-layer Janus patch is developed, whose inner layer facing the operated tendon is a multifunctional electrospun hydrogel patch (MEHP), encircled further by a poly-l-lactic acid (PLLA) fibrous outer layer facing the surrounding tissue. Specifically, MEHP is prepared by gelatin methacryloyl (GelMA) and zinc oxide (ZnO) nanoparticles, which are co-electrospun first and then treated by tannic acid (TA). The inner MEHP exhibits superior mechanical performance, adhesion strength, and outstanding antioxidation, anti-inflammation, and antibacterial properties, and it can adhere to the injury site offering a favorable microenvironment for tendon regeneration. Meanwhile, the outer PLLA acts as a physical barrier that prevents extrinsic cells and tissues from invading the defect site, reducing peritendinous adhesion formation. This work presents a proof-of-concept of a drug-free graft with anisotropic adhesive and biological functions to concert the healing phases of injured tendon by alleviating incipient inflammation and oxidative damage but supporting tissue regeneration and reducing tendon adhesion in the later phase of repair and remodeling. It is envisioned that this Janus patch could offer a promising strategy for safe and efficient tendon therapy.

Blockade of CD155 and Interleukin-6 Suppresses Breast Cancer Cell Growth

Background: Breast cancer is the foremost common type of cancer worldwide and the leading cause of death related to cancer. Poliovirus receptor (CD155) or nectin-like molecule-5 expression has been shown to increase in tumor cells and bind to the DNAX accessory molecule (DNAM-1)/T cell immunoreceptor with Ig and ITIM domains (TIGIT)/CD69 ligand present on the surface of T and natural killer cells, increasing inflammatory cytokines, including interleukin 6 (IL-6) in the tumor microenvironment. As a result, we intended to simultaneously target both CD155 and IL-6 as an effective therapeutic approach to prevent breast cancer growth. Methods: In this study, 4T1 cells were transfected with small interfering RNA (siRNA) molecules against CD155 and IL-6, using lipofectamine (LP). Target gene expression was analyzed using both the real-time polymerase chain reaction (RT-PCR) and an enzyme-linked immunosorbent assay (ELISA). The methyl thiazolyl tetrazolium (MTT) assay also examined the cytotoxic effect of combined therapy. Results: The results showed that the cells were effectively transfected with LP, resulting in the downregulation of IL-6 and CD155. In addition, the combined silencing of IL-6 and CD155 potently reduced the cellular viability of cancer cells. Conclusion: These findings revealed that the simultaneous targeting of CD155 and IL-6 in breast cancer cells (4T1) is an innovative and efficient therapy strategy to induce apoptosis in malignant cells.

Antitumor Effects of a Distinct Sonodynamic Nanosystem through Enhanced Induction of Immunogenic Cell Death and Ferroptosis with Modulation of Tumor Microenvironment.

Sonodynamic therapy (SDT) holds great promise to be applied for cancer therapy in clinical settings. However, its poor therapeutic efficacy has limited its applications owing to the apoptosis-resistant mechanism of cancer cells. Moreover, the hypoxic and immunosuppressive tumor microenvironment (TME) also weakens the efficacy of immunotherapy in solid tumors. Therefore, reversing TME remains a formidable challenge. To circumvent these critical issues, we developed an ultrasound-augmented strategy to regulate the TME by utilizing an HMME-based liposomal nanosystem (HB liposomes), which can synergistically promote the induction of ferroptosis/apoptosis/immunogenic cell death (ICD) and initiate the reprograming of TME. The RNA sequencing analysis demonstrated that apoptosis, hypoxia factors, and redox-related pathways were modulated during the treatment with HB liposomes under ultrasound irradiation. The in vivo photoacoustic imaging experiment showed that HB liposomes enhanced oxygen production in the TME, alleviated TME hypoxia, and helped to overcome the hypoxia of the solid tumors, consequently improving the SDT efficiency. More importantly, HB liposomes extensively induced ICD, resulting in enhanced T-cell recruitment and infiltration, which normalizes the immunosuppressive TME and facilitates antitumor immune responses. Meanwhile, the HB liposomal SDT system combined with PD1 immune checkpoint inhibitor achieves superior synergistic cancer inhibition. Both in vitro and in vivo results indicate that the HB liposomes act as a sonodynamic immune adjuvant that is able to induce ferroptosis/apoptosis/ICD via generated lipid-reactive oxide species during the SDT and reprogram TME due to ICD induction. This sonodynamic nanosystem integrating oxygen supply, reactive oxygen species generation, and induction of ferroptosis/apoptosis/ICD is an excellent strategy for effective TME modulation and efficient tumor therapy.

Hydroxysafflor yellow A-loaded biomimetic liposomes alleviate HHcy-induced atherosclerosis by regulating methylation related autophagy

Cardiovascular disease (CVD) caused by atherosclerosis has become a main threaten for human health. As an independent risk factor, hyperhomocysteinemia (HHcy) played an important role in the pathogenesis of atherosclerosis by regulating DNA methylation modification and autophagy of macrophages. In this study, we constructed a new kind of macro-liposome nanoparticle by hybridizing liposome with macrophages membranes (Møm) to encapsulate hydroxysafflower yellow A (HSYA). Assertion of Hyaluronic acid (HA) on the macro-liposome NPs was adopted to endow nanodrug targeting ability. In vitro results showed that the prepared macro-liposome nanoparticles can significantly inhibit Atg13 DNA methylation, while enhance autophagy of macrophages to promote cholesterol efflux, as well. In vivo studies have shown that the HA modification made the macro-liposome NPs an ideal decoy for targeting plaques. Thus, the macro-liposome NPs with prolonged blood circulation time, and improved targeting ability can achieve optimal HSYA accumulation at the region of atherosclerotic plaques to obtain high efficacy. According to our point, the nano-drug delivery system with high immune escape capability provided a feasible therapeutic strategy for efficient atherosclerosis therapy.

NIR regulated upconversion nanoparticles@metal-organic framework composite hydrogel dressing with catalase-like performance and enhanced antibacterial efficacy for accelerating wound healing

Developing a hydrogel dressing with excellent antibacterial efficacy for accelerating wound healing is high desirable in clinical applications. In this work, NIR regulated metal-organic framework composite hydrogel dressing was constructed for enhanced antibacterial efficacy and accelerated wound healing via the compounding between hydrogel and UCNPs@ZrMOF-Pt nanoparticles. The visible light emitted from upconvertion nanoparticles (UCNPs) activated porphyrin based metal-organic framework (MOF) in composite hydrogel to generate 1O2 for photodynamic antibacterial therapy under NIR laser irradiation. Moreover, the UCNPs@ZrMOF-Pt in composite hydrogel with catalase-like performance could effectively convert the high concentration H2O2 in wound to abundant O2, which relieved the hypoxic in infected wound. Thus, the photodynamic antibacterial efficacy was remarkably enhanced, leading to accelerate the wound healing. This work presented a novel strategy for high efficient antibacterial therapy and accelerated wound healing.

Degradable Fe3O4-based nanocomposite for cascade reaction-enhanced anti-tumor therapy.

Cascade catalytic therapy has been recognized as a promising cancer treatment strategy, which is due in part to the induced tumor apoptosis when converting intratumoral hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (˙OH) based on the Fenton or Fenton-like reactions. Moreover this is driven by the efficient catalysis of glucose oxidization associated with starving therapy. The natural glucose oxidase (GO x ), recognized as a "star" enzyme catalyst involved in cancer treatment, can specially and efficiently catalyze the glucose oxidization into gluconic acid and H2O2. Herein, pH-responsive biodegradable cascade therapeutic nanocomposites (Fe3O4/GO x -PLGA) with dual enzymatic catalytic features were designed to respond to the tumor microenvironment (TME) and to catalyze the cascade reaction (glucose oxidation and Fenton-like reaction) for inducing oxidase stress. The GO x -motivated oxidation reaction could effectively consume intratumoral glucose to produce H2O2 for starvation therapy and the enriched H2O2 was subsequently converted into highly toxic ˙OH by a Fe3O4-mediated Fenton-like reaction for chemodynamic therapy (CDT). In addition, the acidity amplification owing to the generation of gluconic acid will in turn accelerate the degradation of the nanocomposite and initiate the Fe3O4-H2O2 reaction for enhancing CDT. The resultant cooperative cancer therapy was proven to provide highly efficient tumor inhibition on HeLa cells with minimal systemic toxicity. This cascade catalytic Fenton nanocomposite might provide a promising strategy for efficient cancer therapy.

Advances in nanomedicine for the treatment of infectious diseases caused by viruses.

Viruses have a worldwide impact on healthcare and social and economic growth because they are the largest cause of mortality due to infectious diseases. Furthermore, the long-term conventional drug use comes with substantial risks to public health, such as the rapid evolution of drug resistance and the emergence of secondary side effects. Therefore, it is necessary to develop new methods for the treatment of virus-related diseases. In this case, the use of nanomaterial-based nanomedicines possesses tremendous advantages over the traditional treatment approach. Nanomaterial-based drug delivery systems have unique features that make them promising candidates in the pursuit of therapeutic benefits. In this review, we present the various biocompatible nanomaterials that show promise as nanomedicines for anti-viral therapy. Also, we include how current developments in nanomedicine are being used to treat and prevent the most common viral illnesses such as the flu, HIV, SARS-CoV-2, monkeypox, and human papillomaviruses.

Cell membrane-camouflaged liposomes and neopeptide-loaded liposomes with TLR agonist R848 provides a prime and boost strategy for efficient personalized cancer vaccine therapy

Recent advances in bioinformatics and nanotechnology offer great opportunities for personalized cancer vaccine development. However, the timely identification of neoantigens and unsatisfactory efficacy of therapeutic cancer vaccines remain two obstacles for clinical transformation. We propose a “prime and boost” strategy to facilitate neoantigen-based immunotherapy. To prime the immune system, we first constructed personalized liposomes with cancer cell membranes and adjuvant R848 to provide immunostimulatory efficacy and time for identifying tumor antigens. Liposomes loaded with personalized neopeptides and adjuvants were used to boost the immune response. In vitro experiments verified potent immune responses, including macrophage polarization, dendritic cell maturation, and T lymphocyte activation. In vivo B16F10 and TC-1 cancer model were used to investigate efficient tumor growth suppression. Liposomal vaccines with neopeptides could stimulate human dendritic cells and T lymphocytes in vitro. These results demonstrate that the “prime and boost” strategy provides simple, quick, and efficient personalized vaccines for cancer therapy.

Biocatalytic Depletion of Tumorigenic Energy Sources Driven by Cascade Reactions for Efficient Antitumor Therapy

Glucose and lactate play important roles for tumor growth. How to simultaneously deprive tumors of glucose and lactate is a big challenge. We have developed a cascade catalytic system (denoted as FPGLC) based on fluorinated polymer (FP) with co-loading of glucose oxidase (GOx), lactate oxidase (LOx), and catalase (CAT). GOx and LOx deprive glucose and lactate, respectively, resulting in abundant hydrogen peroxide (H2O2) generation. Meanwhile, CAT catalyzes H2O2 into O2, which not only promotes catalytic reactions of GOx and LOx for consuming more glucose and lactate, but also alleviates tumor hypoxia. Benefiting from the excellent cross-membrane and transmucosal penetration capacities of FP, FPGLC rapidly accumulated in tumors and subsequently mediated enhanced cascade catalytic therapy under the guidance of photoacoustic imaging. These results demonstrate that the dual depletion of glucose and lactate with O2 supply is a promising strategy for efficient antitumor starvation therapy.

Biocatalytic Depletion of Tumorigenic Energy Sources Driven by Cascade Reactions for Efficient Antitumor Therapy.

Glucose and lactate play important roles for tumor growth. How to simultaneously deprive tumors of glucose and lactate is a big challenge. We have developed a cascade catalytic system (denoted as FPGLC) based on fluorinated polymer (FP) with co-loading of glucose oxidase (GOx), lactate oxidase (LOx), and catalase (CAT). GOx and LOx deprive glucose and lactate, respectively, resulting in abundant hydrogen peroxide (H2 O2 ) generation. Meanwhile, CAT catalyzes H2 O2 into O2 , which not only promotes catalytic reactions of GOx and LOx for consuming more glucose and lactate, but also alleviates tumor hypoxia. Benefiting from the excellent cross-membrane and transmucosal penetration capacities of FP, FPGLC rapidly accumulated in tumors and subsequently mediated enhanced cascade catalytic therapy under the guidance of photoacoustic imaging. These results demonstrate that the dual depletion of glucose and lactate with O2 supply is a promising strategy for efficient antitumor starvation therapy.

Tumor-Microenvironment-Responsive Cascade Reactions by a Cobalt-Single-Atom Nanozyme for Synergistic Nanocatalytic Chemotherapy.

Nanocatalytic therapy, involving the nanozyme-triggered production of reactive oxygen species (ROS) in the tumor microenvironment (TME), has demonstrated potential in tumor therapy, but nanozymes still face challenges of activity and specificity that compromise the therapeutic efficacy. Herein, we report a strategy based on a single-atom nanozyme to initiate cascade enzymatic reactions in the TME for tumor-specific treatment. The cobalt-single-atom nanozyme, with Co-N coordination on N-doped porous carbon (Co-SAs@NC), displays catalase-like activity that decomposes cellular endogenous H2 O2 to produce O2 , and subsequent oxidase-like activity that converts O2 into cytotoxic superoxide radicals to efficiently kill tumor cells. By incorporation with doxorubicin, the therapy achieves a significantly enhanced antitumor effect in vivo. Our findings show that cascade TME-specific catalytic therapy combined with chemotherapy is a promising strategy for efficient tumor therapy.