Cell membrane-camouflaged nanoparticles possess inherent advantages derived from their membrane structure and surface antigens, including prolonged circulation in the bloodstream, specific cell recognition and targeting capabilities, and potential for immunotherapy. Herein, we introduce a cell membrane biomimetic nanodrug platform termed MPB-3BP@CM NPs. Comprising microporous Prussian blue nanoparticles (MPB NPs) serving as both a photothermal sensitizer and carrier for 3-bromopyruvate (3BP), these nanoparticles are cloaked in a genetically programmable cell membrane displaying variants of signal regulatory protein α (SIRPα) with enhanced affinity to CD47. As a result, MPB-3BP@CM NPs inherit the characteristics of the original cell membrane, exhibiting an extended circulation time in the bloodstream and effectively targeting CD47 on the cytomembrane of colorectal cancer (CRC) cells. Notably, blocking CD47 with MPB-3BP@CM NPs enhances the phagocytosis of CRC cells by macrophages. Additionally, 3BP, an inhibitor of hexokinase II (HK2), suppresses glycolysis, leading to a reduction in adenosine triphosphate (ATP) levels and lactate production. Besides, it promotes the polarization of tumor-associated macrophages (TAMs) towards an anti-tumor M1 phenotype. Furthermore, integration with MPB NPs-mediated photothermal therapy (PTT) enhances the therapeutic efficacy against tumors. These advantages make MPB-3BP@CM NPs an attractive platform for the future development of innovative therapeutic approaches for CRC. Concurrently, it introduces a universal approach for engineering disease-tailored cell membranes for tumor therapy.

Antibacterial photocatalytic therapy (APCT) is one of the most promising non-antibiotic treatment strategies for biofilm-infected wounds and inflammation caused by drug-resistant bacteria. However, it still faces issues such as inadequate single antibacterial capacity and lack of antioxidant capacity. In this study, a Z-scheme heterojunction (Bi2S3-X@PDA) is designed using a polydopamine (PDA) shell firmly anchored to the surface of sulfur vacancy-rich bismuth sulfide nanorods (Bi2S3-X NRs). Under near-infrared light and hydrogen peroxide, Bi2S3-X@PDA significantly improves the photocatalytic efficiency of reactive oxygen species generation and shows a nearly 100% broad-spectrum antibacterial effect against multiple bacterial strains and bacterial biofilms in vitro. Interestingly, the antioxidant activity of the PDA shell in Bi2S3-X@PDA remarkably downregulates the expression of pro-inflammatory factors and promotes macrophage reprogramming toward the proregenerative M2 phenotype. In a mouse wound model of methicillin-resistant Staphylococcus aureus biofilm infection, Bi2S3-X@PDA effectively eliminates drug-resistant bacterial biofilms through APCT/mild photothermal therapy, while reducing inflammation in normal tissues and regulating the immune microenvironment, thereby promoting rapid wound healing. Overall, this light-controlled treatment strategy, which provides both antibacterial and anti-inflammatory functions, is a reliable tool for combating biofilm infection and inflammation caused by drug-resistant bacteria.

Camptothecin (CPT) exhibits potent antitumor activity; however, its clinical application is limited by significant gastrointestinal adverse effects (GAEs). Although the severity of GAEs associated with CPT derivatives has decreased, the incidence rate of these adverse effects has remained high. CPT multifunctional nanoparticles (PCRHNs) have the potential to increase the efficacy of CPT while reducing side effects in major target organs; however, the impact of PCRHNs on the GAEs from CPT remains uncertain. Here, we investigated the therapeutic effects of PCRHNs and different doses of CPT and examined their impacts on the intestinal barrier and the intestinal microbiota. We found that the therapeutic efficacy of PCRHNs + Laser treatment was superior to that of high-dose CPT, and PCRHNs + Laser treatment also provided greater benefits by helping maintain intestinal barrier integrity, intestinal microbiota diversity, and intestinal microbiota abundance. In summary, compared to high-dose CPT treatment, PCRHNs + Laser treatment can effectively balance therapeutic effects and GAEs. A high dose of CPT promotes the enrichment of the pathogenic bacteria Escherichia-Shigella, which may be attributed to diarrhea caused by CPT, thus leading to a reduction in microbial burden; additionally, EscherichiaShigella rapidly grows and occupies niches previously occupied by other bacteria that are lost due to diarrhea. PCRHNs + Laser treatment increased the abundance of Lactobacillus (probiotics), possibly due to the photothermal effect of the PCRHNs. This effect increased catalase activity, thus facilitating the conversion of hydrogen peroxide into oxygen within tumors and increasing oxygen levels in the body, which is conducive to the growth of facultative anaerobic bacteria.

Mitochondria play important roles in angiogenesis. However, the mechanisms remain elusive. In this study, we found that mitochondrial ubiquinol-cytochrome c reductase complex assembly factor 3 (UQCC3) is a key regulator of angiogenesis. TALEN-mediated knockout of Uqcc3 in mice caused embryonic lethality at 9.5-10.5 days postcoitum, and vessel density was dramatically reduced. Similarly, knockout of uqcc3 in zebrafish induced lethality post-fertilization and impaired vascular development. Knockout of UQCC3 resulted in slower tumor growth and angiogenesis. Mechanistically, UQCC3 was upregulated under hypoxia, promoted reactive oxygen species (ROS) generation, enhanced HIF-1 alpha stability and increased VEGF expression. Finally, higher expression of UQCC3 was associated with poor prognosis in multiple types tumors, implying a role for UQCC3 in tumor progression. In conclusion, our findings highlight the important contribution of UQCC3 to angiogenesis under both physiological and pathological conditions, indicating the potential of UQCC3 as a therapeutic target for cancer.

Osteoarthritis (OA) is a common joint condition that is a leading cause of disability worldwide. There are currently no disease-modifying treatments for osteoarthritis, which is associated with multiple kinds of inflammatory cytokines produced by M1 macrophages in the synovium of the joint. Despite recent therapeutic advancements with anti-cytokine biologics, the OA therapy response rate continues to be inadequate. To treat OA, the pro-inflammatory and anti-inflammatory responses of synoviocytes and macrophages must be controlled simultaneously. Therefore, the immune regulation capabilities of an ideal nano-drug should not only minimize pro-inflammatory responses but also effectively boost anti-inflammatory responses. In this paper, an M2H@RPK nanotherapeutic system was developed, KAFAK and shRNA-LEPR were condensed with polyethylenimine (PEI) to form a complex, which was then modified with hyaluronic acid (HA) to negatively charge to cover the M2 membrane. It was discovered that the repolarization of macrophages from the M1 to the M2 phenotype lowered pro-inflammatory responses while enhancing anti-inflammatory responses in macrophages and synoviocytes. In vitro and in vivo studies demonstrate that M2H@RPK dramatically decreases proinflammatory cytokines, controls synovial inflammation, and provides significant therapeutic efficacy by reducing joint damage. Overall, it has been demonstrated that M2H@RPK provides inflammation-targeted therapy by macrophage repolarization, and it represents a promising OA therapeutic strategy.

Patients with colorectal cancer (CRC) and diffuse peritoneal metastasis (PM) are not eligible for surgical intervention. Thus, palliative treatment remains the standard of care in clinical practice. Systemic chemotherapy fails to cause drug accumulation at the lesion sites, while intraperitoneal chemotherapy (IPC) is limited by high clearance rates and associated complications. Given the poor prognosis, a customized OxP/R848@PLEL hydrogel delivery system has been devised to improve the clinical benefit of advanced CRC with diffuse PM. This system is distinguished by its simplicity, security, and efficiency. Specifically, the PLEL hydrogel exhibits excellent injectability and thermosensitivity, enabling the formation of drug depots within the abdominal cavity, rendering it an optimal carrier for IPC. Oxaliplatin (OxP), a first-line drug for advanced CRC, is cytotoxic and enhances the immunogenicity of tumors by inducing immunogenic cell death. Furthermore, OxP and resiquimod (R848) synergistically enhance the maturation of dendritic cells, promote the expansion of cytotoxic T lymphocytes, and induce the formation of central memory T cells. Moreover, R848 domesticates macrophages to an anti-tumor phenotype. OxP/R848@PLEL effectively eradicates peritoneal metastases, completely inhibits ascites production, and significantly prolongs mice lifespan. As such, it provides a promising approach to managing diffuse PM in patients with CRC without surgical indications.

Angiogensis during embryonic development and tumor growth requires the crucial involvement of mitochondria, which provide energy for cell proliferation, produce angiogenic signaling molecules, and exhibit a different functional profile in these cells. However, the detailed mechanisms underlying the regulatory role of mitochondria in angiogenesis remain elusive and warrant. Here, we reported that a small assembly factor of complex III, ubiquitin-cytochrome c reductase complex assembly factor 3 (UQCC3), is indispensable for angiogenesis during embryonic development and tumor growth. Homozygous deletion of UQCC3 caused early embryonic lethality and impaired vascular development. UQCC3 knockout in tumor cells impaired tumor angiogenesis and inhibits tumor growth. Mechanistically, UQCC3 expression was significantly upregulated in a hypoxic environment, which stabilised hypoxia inducible factor-1α (HIF-1α) and provoked a significantly higher expression of VEGF. UQCC3 knockout reduced the production of mitochondrial reactive oxygen species (ROS), stabilzed HIF-1α, and VEGF expression, but supplementation of ROS can restore HIF-1α and VEGF levels, and vice versa. Finally, based on the analysis of TCGA database, having high levels of UQCC3 is associated with unfavorable outcomes across various types of tumors, indicating a significant role for UQCC3 in tumor progression.

Bladder cancer is one of the most common malignant tumors in the urinary system worldwide. The poor permeability and uncontrollable release of drug and hypoxia of tumor tissues were the main reasons leading to poor therapeutic effect of chemo-photodynamic therapy for bladder cancer. To solve the above problems, a tumor-targeting peptide Arg-Gly-Asp (RGD) modified platinum nanozyme (PtNP) co-loaded glutathione (GSH)-responsive prodrug nanoparticles (PTX-SS-HPPH/Pt@RGD-NP) was constructed. Firstly, a GSH-responsive prodrug (PTX-SS-HPPH) was prepared by introducing a disulfide bond between paclitaxel (PTX) and photosensitizer 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH), which could realize the GSH-responsive release of the drug at the tumor sites. Also, the distearoylphosphoethanolamine-poly (ethylene glycol)-RGD peptide (DSPE-PEG-RGD) modified the prodrug to enhance the targeting and permeability ability to bladder cancer cells. Besides, to alleviate the hypoxia of tumor tissues, PtNP was introduced to produce oxygen (O2) and improve photodynamic therapy efficiency. The results showed that the PTX-SS-HPPH/Pt@RGD-NP could achieve GSH-responsive drug release in tumor microenvironment, enhance the drug accumulation time and permeability at tumor sites in T24 subcutaneous tumor model and T24 orthotopic bladder tumor model, and alleviate hypoxia in tumor tissues, thus realizing enhanced chemo-photodynamic therapy for bladder cancer, and providing new strategies and methods for clinical treatment of bladder cancer.

Oxidative stress (OS), characterized by the excessive accumulation of reactive oxygen species (ROS), is an emerging hallmark of cancer. Tumorigenesis and development driven by ROS require an aberrant redox homeostasis, that activates onco-signaling and avoids ROS-induced programmed death by orchestrating antioxidant systems. These processes are revealed to closely associate with noncoding RNAs (ncRNAs). On the basis of the available evidence, ncRNAs have been widely identified as multifarious modulators with the involvement of several key redox sensing pathways, such as NF-κB and Nrf2 signaling, therefore potentially becoming effective targets for cancer therapy. Furthermore, the vast majority of ncRNAs with property of easy detected in fluid samples (e.g., blood and urine) facilitate clinicians to monitor redox homeostasis, indicating a novel method for cancer diagnosis. Herein, focusing on carcinoma initiation, metastasis and chemoradiotherapy resistance, we aimed to discuss the ncRNAs-ROS network involved in cancer progression, and the potential clinical application as biomarkers and therapeutic targets.

Improving the efficacy of melanoma treatment remains an important global challenge. Here, we combined chemotherapy with protein tyrosine phosphatase nonreceptor type 2(Ptpn2) based immunotherapy in an effort to address this challenge. Short-hairpin RNA (shRNA) targeting Ptpn2 was coencapsulated with doxorubicin (DOX) in the cell membrane of M1 macrophages (M1HD@RPR). The prepared nanoparticles (NPs) were effectively phagocytosed by B16F10 cells and M1 macrophages, but not by M0 macrophages. Hence, NP evasion from the reticuloendothelial system (RES) was improved and NP enrichment in tumor sites increased. M1HD@RPR can directly kill tumor cells and stimulate immunogenic cell death (ICD) by DOX and downregulate Ptpn2. It can promote M1 macrophage polarization and dendritic cell maturation and increase the proportion of CD8+ T cells. M1HD@RPR killed and inhibited the growth of primary melanoma and lung metastatic tumor cells without harming the surrounding tissue. These findings establish M1HD@RPR as a safe multifunctional nanoparticle capable of effectively combining chemotherapy and gene immunotherapies against melanoma.

Breast cancer has become the most commonly diagnosed cancer type in the world. A combination of chemotherapy and photothermal therapy (PTT) has emerged as a promising strategy for breast cancer therapy. However, the intricacy of precise delivery and the ability to initiate drug release in specific tumor sites remains a challenging puzzle. Therefore, to ensure that the therapeutic agents are synchronously delivered to the tumor site for their synergistic effect, a multifunctional nanoparticle system (PCRHNs) is developed, which is grafted onto the prussian blue nanoparticles (PB NPs) by reductionresponsive camptothecin (CPT) prodrug copolymer, and then modified with tumor-targe ting peptide cyclo(Asp-D-Phe-Lys-Arg-Gly) (cRGD) and hyaluronic acid (HA). PCRHNs exhibited nano-sized structure with good monodispersity, high load efficiency of CPT, triggered CPT release in response to reduction environment, and excellent photothermal conversion under laser irradiation. Furthermore, PCRHNs can act as a photoacoustic imaging contrast agent-guided PTT. In vivo studies indicate that PCRHNs exhibited excellent biocompatibility, prolonged blood circulation, enhanced tumor accumulation, allow tumor-specific chemo-photothermal therapy to achieve synergistic antitumor effects with reduced systemic toxicity. Moreover, hyperthermia-induced upregulation of heat shock protein 70 in the tumor cells could be inhibited by CPT. Collectively, PCRHNs may be a promising therapeutic way for breast cancer therapy. 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Tumor photothermal therapy (PTT) has spatiotemporal controllability, is minimally invasive, has high selectivity for local cancers, and has a good anti-cancer effect; thus, it has been confirmed as a promising cancer treatment. However, regional high temperatures during treatment may damage normal tissues and even induce inflammation and tumor metastasis. In this study, a multifunctional cascade nanoreactor based on hollow mesoporous silica (HMSN) was prepared by loading a photothermal agent (PTA) prodrug of 3,3′,5,5′-tetramethylbenzidine (TMB), glucose oxidase (Gox), and horseradish peroxidase (HRP), which are used for the synergistic cancer therapy of starvation therapy (ST) and PTT. First, the adenosine triphosphate(ATP) generation of tumor cells was obstructed using Gox-mediated starvation therapy, and the heat shock protein-70 (HSP-70) level was further used to reduce the thermo-resistance. Then, HRP improved the hypoxic state of the tumor microenvironment (TME) by consuming H2O2 and further oxidizing the colorless TMB(PTA prodrug) into OXTMB (PTA) with an excellent photothermal effect. In addition,the glutathione(GSH) level of the tumor cells was also downregulated, which further promoted the process of apoptosis. Ultimately, both the in-vivo and in-vitro studies showed that the nanoreactor significantly inhibited the growth of tumor cells and ablated the solid tumor, which provides another possibility for clinical intervention.

Hypoxia is known to stimulate mitochondrial reactive oxygen species (mROS) in cells. Here, we present a detailed protocol to detect mROS using MitoSOX staining in live cells under normoxia and hypoxia. Flow cytometry allows sensitive and reliable quantification of mROS by FlowJo software. We optimized several aspects of the procedure including hypoxic treatment, working concentrations of the staining buffer, and quantitative analyses. Here, we use HepG2 cells, but the protocol can be applied to other cell lines. For complete details on the use and execution of this protocol, please refer to Yang et al. (2020).

Focal therapy, or partial gland ablation, represents the middle ground between active surveillance and definitive treatment strategies against localized prostate cancer (PCa), among which the ultrasound- and light-mediated focal therapies are quite promising. Herein, for the first time in the literature, a novel polysaccharide-based nanoprodrug is fabricated for synergistic sonodynamic therapy and phototherapy against localized PCa. Specifically, the cyanine dye IR806 is conjugated to chondroitin sulfate (CS) via disulfide linkages to obtain CS-ss-IR806 (CSR) conjugates, which then self-assemble to form CSR nanoparticles (NPs) with properties of enhanced endocytosis, redox/hyaluronidase-responsiveness, and mitochondria-targeted ability. In contrast to free sensitizers, CSR NPs reveal dramatically enhanced water solubility, substantially lower dark toxicity, and superior biocompatibility. Encouragingly, favorable hyperthermia and high reactive oxygen species generation are observed on exposing CSR NPs to combined sono/photoirradiation. In a PCa tumor-bearing mice model, intratumoral injection with a markedly low dose of CSR NPs followed by dual-irradiation results in superior trimodal anticancer efficacy when compared with either monoirradiation strategy. Such synergistic antitumor efficacy is further demonstrated to be associated with the common and complementary mechanisms of sonotherapy and phototherapy. This work provides a promising approach as a next-generation focal therapy strategy against localized PCa.

Dear Editor, Chimeric antigen receptor modified T(CAR-T)cell therapy has shown potent antitumor activity against relapsed and refractory hematological malignancies.However,its efficacy in solid tumors is limited,1 partly because of the inhibition of PD-L1/PD-1 signaling on CAR-T cells in solid tumors.Further optimizations of CAR-T cells by disrupting PD-1 signaling have improved the anti-tumor efficacy of CAR-T cells.2 Here,we report an alternative approach that sensitizes tumor cells by interferon(IFN)-γ,but without modifying T cells;this strategy surmounts PD-1 inhibition and markedly enhances CAR-T anti-tumor activities in vitro and in vivo.

The treatment of large established tumors remains a significant challenge and is generally hampered by poor drug penetration and intrinsic drug resistance of tumor cells in the central tumor region. In the present study, we developed bacterial particles (BactPs) to deliver chemotherapeutics into the tumor mass by hijacking neutrophils as natural cell-based carriers. BactPs loaded with doxorubicin, 5-fluorosuracil, or paclitaxel induced significantly greater tumor regression than unconjugated drugs. This effect was mediated by the ability of BactPs to incorporate chemotherapeutics and serve as vascular disrupting agents that trigger innate host responses and recruit phagocytic neutrophils. Vascular disruption resulted in extensive cell death in the central areas of the tumor mass. Recruited neutrophils acted as natural cellular carriers to deliver engulfed BactPs, which ensured drug delivery into the tumor mass and cytotoxic effects in areas that are normally inaccessible to traditional chemotherapy. Thus, BactPs eradicate large established tumors by functioning as vascular disrupters and natural drug carriers for neutrophil-mediated chemotherapy.

In recent years, Non-Hodgkin lymphoma (NHL) has been one of the most fast-growing malignant tumor diseases. NHL poses severe damages to physical health and a heavy burden to patients. Traditional therapies (chemotherapy or radiotherapy) bring some benefit to patients, but have severe adverse effects and do not prevent relapse. The relevance of emerging immunotherapy options (immune-checkpoint blockers or adoptive cellular methods) for NHL remains uncertain, and more intensive evaluations are needed. In this work, inspired by the idea of vaccination to promote an immune response to destroy tumors, we used a biomaterial-based strategy to improve a tumor cell-based vaccine and constructed a novel vaccine named Man-EG7/CH@CpG with antitumor properties. In this vaccine, natural tumor cells are used as a vector to load CpG-ODN, and following lethal irradiation, the formulations were decorated with mannose. The study of the characterization of the double-improved vaccine evidenced the enhanced ability of DCs targeting and improved immunocompetence, which displayed an antitumor function. In the lymphoma prevention model, the Man-EG7/CH@CpG vaccine restrained tumor formation with high efficiency. Furthermore, unlike the non-improved vaccine, the double-improved vaccine elicited an enhanced antitumor effect in the lymphoma treatment model. Next, to improve the moderate therapeutic effect of the mono-treatment method, we incorporated a chemotherapeutic drug (doxorubicin, DOX) into the process of vaccination and devised a combination regimen. Fortunately, a tumor inhibition rate of ~85% was achieved via the combination therapy, which could not be achieved by mono-chemotherapy or mono-immunotherapy. In summary, the strategy presented here may provide a novel direction in the establishment of a tumor vaccine and is the basis for a prioritization scheme of immuno-chemotherapy in enhancing the therapeutic effect on NHL.

Photodynamic therapy (PDT) is a relatively safe and clinically promising treatment to combat primary tumors, especially epidermal carcinoma, while has negligible effects on distant metastasis. Therefore, this work reports a multifunctional nanosystem (HPR@CCP) exerting a combined photodynamic and immunotherapy to amplify the therapeutic effect on primary tumors and distant metastasis. Specifically, this nanosystem was obtained by electrostatic adsorption of a negatively charged hyaluronic acid “shell” with a positively charged “core” consisting of the CRISPR-Cas9 system targeting the Ptpn2 gene (Cas9-Ptpn2) and a modified mitochondria-targeting chlorin e6 (TPP-PEI-Ce6). Cell experiments demonstrated that the HPR@CCP nanoparticles possessed very high transfection efficiency on B16F10 cells, and TPP-PEI-Ce6 in the nanoparticles resulted in a significant PDT efficacy due to the efficient singlet oxygen generation in mitochondria under laser-irradiation. The accumulation of the nanoparticles in the tumor by active and passive tumor-targeting in vivo led to the disruption of the Ptpn2 gene by the Cas9-Ptpn2 plasmids in the nanocarriers, thus sensitizing tumors to immunotherapy by the increase of the IFN-γ and TNF-α signaling and the promotion of the proliferation of CD8+ T cells. In addition, Hyaluronidase was administered in advance to destroy the hyaluronic acid in the condensed extracellular matrix and to remove the hyaluronic acid “shell” from the nanosystem, subsequently leading to an enhanced penetration of oxygen and therapeutic agents. Fortunately, the primary and distant tumors in the experimental animals were remarkably inhibited after the combination of PDT-immunotherapy, thus, this easy-to-built nanomedicine could be used as a potential combination therapy against tumors.

Bioenergetic reprogramming during hypoxia adaption is critical to promote hepatocellular carcinoma (HCC) growth and progression. However, the mechanism underlying the orchestration of mitochondrial OXPHOS (oxidative phosphorylation) and glycolysis in hypoxia is not fully understood. Here, we report that mitochondrial UQCC3 (C11orf83) expression increases in hypoxia and correlates with the poor prognosis of HCC patients. Loss of UQCC3 impairs HCC cell proliferation in hypoxia in vitro and in vivo. Mechanistically, UQCC3 forms a positive feedback loop with mitochondrial reactive oxygen species (ROS) to sustain UQCC3 expression and ROS generation in hypoxic HCC cells and subsequently maintains mitochondrial structure and function and stabilizes HIF-1α expression to enhance glycolysis under hypoxia. Thus, UQCC3 plays an indispensable role for bioenergetic reprogramming of HCC cells during hypoxia adaption by simultaneously regulating OXPHOS and glycolysis. The positive feedback between UQCC3 and ROS indicates a self-modulating model within mitochondria that initiates the adaptation of HCC to hypoxic stress.

Due to hypoxia and poor circulation in the tumor interior, malignant cells in solid tumors are resistant to traditional therapies. In the present study, we reported that bacterial particles (BactPs) functioned effectively in retarding tumor growth as a novel vascular disrupting agent. The BactPs were inactivated intact bacteria. Intravenous administration of BactPs extensively disrupted vessels in the tumor interior, but not in normal organs, and resulted in tumor hemorrhage and necrosis in six hours. We revealed that the extensive disruption of tumor vasculature was due to drastic changes in the inflammatory factors in mice sera and the tumor microenvironments, indicating the critical role of the host immune response to the BactPs. Furthermore, we showed that a combination of six inflammatory cytokines was capable of inducing tumor hemorrhage and necrosis, similar to the effects of the BactPs. Together, these results suggest that BactPs are a novel kind of tumor vascular disruptor with a promising potential for solid tumor treatment.