Given the unique capabilities of natural cell membranes, such as prolonged blood circulation and homotypic targeting, extensive research has been devoted to developing cell membrane-inspired nanocarriers for cancer therapy, while most focused on overcoming one or a few biological barriers. In fact, the journey of nanosystems from systemic circulation to tumor cells involves intricate processes, encompassing blood circulation, tissue accumulation, cancer cell targeting, endocytosis, endosomal escape, intracellular trafficking to target sites, and therapeutic action, all of which pose limitations to their clinical translation. This underscores the necessity of meticulously considering these biological barriers in the design of cell membrane-mimetic nanocarriers. In this review, we delineate the functions and applications of diverse types of cell membranes in nanocarrier systems. We elaborate on the biological hurdles encountered at each stage of the biomimetic nanoparticle’s odyssey to the target, and comprehensively discuss the obstacles imposed by the tumor microenvironment for precise delivery. Subsequently, we systematically review contemporary cell membrane-based strategies aimed at overcoming these multi-level biological barriers, encompassing hybrid cell membrane (HCM) camouflage, tumor microenvironment remodeling, endosomal/lysosomal escape, multidrug resistance (MDR) reversal, optimization of nanoparticle physicochemical properties, and so on. Finally, we outline potential strategies to accelerate the development of cell membrane-inspired precision nanocarriers and discuss the challenges that must be addressed to enhance their clinical applicability. This review serves as a guide for refining the study of cell membrane-mimetic nanosystems in surmounting in vivo delivery barriers, thereby significantly contributing to advancing the development and application of cell membrane-based nanoparticles in cancer delivery.

Leukemia cells prevent immune system from clearing tumor cells by inducing the immunosuppression of the bone marrow (BM) microenvironment. In recent years, further understanding of the BM microenvironment and immune landscape of leukemia has resulted in the introduction of several immunotherapies, including checkpoint inhibitors, T-cell engager, antibody drug conjugates, and cellular therapies in clinical trials. Among them, the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis is a significant checkpoint for controlling immune responses, the PD-1 receptor on tumor-infiltrating T cells is bound by PD-L1 on leukemia cells. Consequently, the activation of tumor reactive T cells is inhibited and their apoptosis is promoted, preventing the rejection of the tumor by immune system and thus resulting in the occurrence of immune tolerance. The PD-1/PD-L1 axis serves as a significant mechanism by which tumor cells evade immune surveillance, and PD-1/PD-L1 checkpoint inhibitors have been approved for the treatment of lymphomas and varieties of solid tumors. However, the development of drugs targeting PD-1/PD-L1 in leukemia remains in the clinical-trial stage. In this review, we tally up the basic research and clinical trials on PD-1/PD-L1 inhibitors in leukemia, as well as discuss the relevant toxicity and impacts of PD-1/PD-L1 on other immunotherapies such as hematopoietic stem cell transplantation, bi-specific T-cell engager, chimeric antigen receptor T-cell immunotherapy.

Nuciferine, a major aporphine alkaloid constituent of lotus leaves, is a raw material for obesity treatment. Extensive studies have revealed that obesity is associated with pancreatic cancer (PC). However, it has not been clarified whether nuciferine could be used in PC treatment or prevention. Here, we show that nuciferine could enhance the sensitivity of PC cells to gemcitabine in both cultured cells and the xenograft mouse model. The mechanism study demonstrated that nuciferine induced YAP Ser127 phosphorylation [pYAP(Ser127)] through AMPK-mediated 3-hydroxy-3-methyl-glutaryl-coA reductase (HMGCR) downregulation. Remarkably, wild-type YAP overexpression or YAP Ser127 mutant could resist to nuciferine and no longer sensitize PC cells to gemcitabine. Knockdown of AMPK attenuated pYAP(Ser127) induced by nuciferine. Moreover, knockdown of AMPK reversed nuciferine-mediated HMGCR downregulation. Notably, HMGCR inhibiting could restrain YAP by phosphorylation Ser 127, and therefore enhance the efficiency of gemcitabine in PC cells. In line with this consistent, overexpression of HMGCR reduced growth inhibition caused by nuciferine and/or gemcitabine treatment in PC cells. In summary, these results provide an effective supplementary agent and suggest a therapeutic strategy to reduce gemcitabine resistance in PC.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood malignancy, deriving from T-cell progenitors in the thymus, and comprises 10-15% of pediatric and 25% of adult primary ALL cases. Despite advances, 20% of pediatric and the majority of adult patients with T-ALL succumb to mortality from resistant or relapsed disease, and the survival rate for patients with resistant or relapsed T-ALL remains poor. Alterations in the expression of Forkhead box protein M1 (FoxM1) have been detected in several types of cancer, and the inhibition of FoxM1 has been investigated as therapeutic strategy in cancer. The present study investigated the effects of the inhibition of FoxM1 by thiostrepton in human T-ALL Jurkat cells. The cells were treated with different concentrations of thiostrepton, either alone or in combination with doxorubicin. Cell viability was measured using CCK-8 assays and the cell cycle distribution, apoptosis and cell-associated mean fluorescence intensity of intracellular doxorubicin were assessed using flow cytometric analysis. The mRNA and protein expression levels were detected by reverse transcription-quantitative polymerase chain reaction and western blot analyses. The inhibition of FoxM1 by thiostrepton significantly decreased the proliferation of the Jurkat cells proliferation in a time- and dose-dependent manner. Cell arrest at the G2/M phase, and apoptosis was significantly increased in the thiostrepton-treated Jurkat cells. Thiostrepton reduced the half maximal inhibitory concentration of doxorubicin in the Jurkat cells, and significantly enhanced the cytotoxicity of doxorubicin within the Jurkat cells by enhancing doxorubicin-induced apoptosis and increasing the accumulation of intracellular doxorubicin. Furthermore, the inhibition of FoxM1 by thiostrepton enhanced doxorubicin-induced apoptosis, possibly through a caspase-3-dependent pathway, and increased the accumulation of intracellular doxorubicin, possibly through downregulating the expression of glutathione S-transferase pi. Collectively, the results of the present study suggested that targeting FoxM1 with thiostrepton resulted in potent antileukemia activity and chemosensitizing effects in human T-ALL Jurkat cells.

Acquired resistance to chemotherapy plays a critical role in human drug treatment failure in many tumor types. Multidrug resistance (MDR) to Adriamycin (ADM) also limits the efficacy of therapy in human chronic myelogenous leukemia (CML). The overexpression of drug efflux transporters is one mechanism uderlying MDR. In particular, the consistent activation of MDR1 and MDR-associated protein 1 (MRP1) is involved in drug resistance. In the present study, ADM-resistant human CML K562/ADM cells were stably transfected with a Tribbles homolog 2 (TRIB2) -targeted vector. A CCK-8 assay showed that the half maximal inhibitory concentration (IC50) of ADM and the cell proliferation were lower in the transfected cells compared with that in the parental K562/ADM cells. The mRNA and protein expression levels of MDR1 and MRP1 were determined by reverse transcription-polymerase chain reaction (RT-PCR), RT-quantitative PCR and western blot analysis. The results showed that the expression of MDR1 and MRP1 was significantly reduced in K562/ADM cells transfected with pGPU6/GFP/Neo-TRIB2. Due to the downregulation of MDR1 and MRP1, the intracellular accumulation of ADM was increased in the transfected cells compared with that in the parental K562/ADM cells. Therefore, the sensitivity of the K562/ADM cells to ADM was enhanced and proliferation was inhibited. Our research revealed that protein expression of the ERK signaling pathway was inhibited by downregulating TRIB2, indicating that the ERK pathway was involved in cell drug resistance and proliferation. Furthermore, we used the ERK-specific blocker U0126 to demonstrate this phenomenon. In summary, our research suggested that knockdown of TRIB2 could slow cell growth and reverse resistance, implying that TRIB2 is a potential therapy target for resistant human CML.

Introduction: As the special modality of cell death, immunogenic cell death (ICD) could activate immune response. Phototherapy in combination with chemotherapy (CT) is a particularly efficient tumor ICD inducing method that could overcome the defects of monotherapies. Methods: In this study, new dual stimuli-responsive micelles were designed and prepared for imaging-guided mitochondrion-targeted photothermal/photodynamic/CT combination therapy through inducing ICD. A dual-sensitive methoxy-polyethylene glycol-SS-poly(L-γ-glutamylglutamine)-SS-IR780 (mPEG-SS-PGG-SS-IR780) polymer was synthesized by grafting IR780 with biodegradable di-carboxyl PGG as the backbone, and mPEG-SS-PGG-SS-IR780/paclitaxel micelles (mPEG-SS-PGG-SS-IR780/PTXL MCs) were synthesized by encapsulating PTXL in the hydrophobic core. Results: In-vivo and -vitro results demonstrated that the three-mode combination micelles inhibited tumor growth and enhanced the therapeutic efficacy of immunotherapy. The dual stimuli-responsive mPEG-SS-PGG-SS-IR780/PTXL MCs were able to facilitate tumor cell endocytosis of nanoparticles. They were also capable of promoting micelles disintegration and accelerating PTXL release. The mPEG-SS-PGG-SS-IR780/PTXL MCs induced mitochondrial dysfunction by directly targeting the mitochondria, considering the thermo- and reactive oxygen species (ROS) sensitivity of the mitochondria. Furthermore, the mPEG-SS-PGG-SS-IR780/PTXL MCs could play the diagnostic and therapeutic roles via imaging capabilities. Conclusion: In summary, this study formulated a high-efficiency nanoscale platform with great potential in combined therapy for tumors through ICD.