Bone Marrow Dendritic Cells Derived Microvesicles for Combinational Immunochemotherapy against Tumor

Various types of cell can change the cytoskeleton and shed microvesicles (MVs) with biomimic properties as parent cells in response to stimuli. To take use of the drug package capability of MVs and the potent antigen presentation property of dendritic cells (DCs), DC‐derived antigenic MVs are constructed by priming DCs with tumor‐derived MVs and then encapsulating a chemotherapeutic drug during MVs shedding. This kind of MVs exhibit significant inhibition on melanoma tumor growth and metastasis. The MV‐encapsulated chemotherapeutics can induce direct cytotoxicity and immunogenic cell death in tumor cells. Moreover, a robust antitumor immunity is induced in both, the tumor‐draining lymph node and the tumor microenvironment as the infiltration and activation of T lymphocytes increases. This kind of MVs is further explored in a hepatic ascites model with remarkable prolonged overall survival of mice. More importantly, the MVs can extend the survival of 60% mice more than 150 d without ascites even after rechallenging the tumor twice. This study demonstrates that antigenic MVs with chemotherapeutics possess great potential in cancer immunochemotherapy.     

Immune Complexes Mimicking Synthetic Vaccine Nanoparticles for Enhanced Migration and Cross‐Presentation of Dendritic Cells

The well‐designed activation of dendritic cells (DCs) by enhancing the delivery of antigens and immunostimulatory adjuvants into DCs is a key strategy for efficient cancer immunotherapy. Antigen‐antibody immune complexes (ICs) are known to directly bind to and cross‐link Fc‐gamma receptors (FcγRs) on DCs, which induce enhanced migration of DCs to draining lymph nodes through the up‐regulation of the chemokine receptor CCR7 and cross‐presentation inducing cytotoxic T lymphocyte (CTL) response against tumor antigen. In this study, ICs mimicking synthetic vaccine nanoparticles (NPs) are designed and synthesized by the coating of poly (lactic‐co‐glycolic acid) (PLGA) NPs containing adjuvant (CpG oligodeoxynuleotides (ODNs) as toll‐like receptor 9 ligands) with ovalbumin (OVA) proteins (as model antigens) and by the formation of OVA–OVA antibody ICs. Through the combination of FcγRs‐mediated efficient antigen uptake and CpG ODNs‐based immunostimulation, the secretion of TNF‐α (12.3‐fold), IL‐6 (7.29‐fold), and IL‐12 (11‐fold), homing ability to lymph nodes (7.5‐fold), and cross‐presentation (83.8‐fold IL‐2 secretion) are dramatically increased in DCs treated with PLGA(IC/CpG) NPs. Furthermore, mice vaccinated with DCs treated with PLGA(IC/CpG) NPs induced significant tumor (EG7‐OVA) growth inhibition as well as prolonged survival through CTL‐mediated enhanced cytotoxicity, antigen‐specific responses, and IFN‐γ secretion.     

Copper Sulfide Nanoparticle-Redirected Macrophages for Adoptive Transfer Therapy of Melanoma

Adoptive cell therapy (ACT) has achieved landmark advances in treating cancer in clinic. Recent advances in ACT of macrophages engineered to express chimeric antigen receptors (CARs) have shown effectiveness in treating solid tumors. However, the CAR-macrophage therapy is dependent on tumor antigen recognition and gene editing methods. Herein, an adoptive macrophage therapy is presented through copper sulfide nanoparticle-regulation that exhibits substantial antitumor effect in melanoma-bearing mice, without the need for tumor antigen repertoire. Bone marrow derived macrophages (BMDMs) incubated with the nanoparticles promote the cellular production of reactive oxygen species (ROS) through dynamin-related protein 1 (Drp1)-mediated mitochodrial fission. The high intracellular ROS level directs BMDMs polarization toward M1 phenotype by classical IKK-dependent NF-κB activation. Moreover, the copper sulfide nanoparticle-stimulated BMDMs (CuS-MΦ) reduce the expression of programmed death-1 (PD-1) and exhibit enhanced phagocytic and digestive ability. Intratumoral transfer of CuS-MΦ significantly prolongs the median survival time of the tumor-bearing mice, remodels the tumor microenvironment, and elicits systemic antitumor immunity. These results suggest a cancer therapeutic approach of adoptively transferred macrophages through the induction of intracellular ROS with nanomaterials.     

Surface Engineered Polymersomes for Enhanced Modulation of Dendritic Cells During Cardiovascular Immunotherapy

The principle cause of cardiovascular disease (CVD) is atherosclerosis, a chronic inflammatory condition characterized by immunologically complex fatty lesions within the intima of arterial vessel walls. Dendritic cells (DCs) are key regulators of atherosclerotic inflammation, with mature DCs generating pro‐inflammatory signals within vascular lesions and tolerogenic DCs eliciting atheroprotective cytokine profiles and regulatory T‐cell (Treg) activation. Here, the surface chemistry and morphology of synthetic nanocarriers composed of poly(ethylene glycol)‐b‐poly(propylene sulfide) copolymers to enhance the targeted modulation of DCs by transporting the anti‐inflammatory agent 1,25‐dihydroxyvitamin D3‐(aVD) and ApoB‐100‐derived antigenic peptide P210 are engineered. Polymersomes decorated with an optimized surface display and density for a lipid construct of the P‐D2 peptide, which binds CD11c on the DC surface, significantly enhance the cytosolic delivery and resulting immunomodulatory capacity of aVD in vitro. Weekly low‐dose intravenous administration of DC‐targeted, aVD‐loaded polymersomes significantly inhibit atherosclerotic lesion development in high‐fat‐diet‐fed ApoE^?/? mice. The results validate the key role of DC immunomodulation during aVD‐dependent inhibition of atherosclerosis and demonstrate the therapeutic enhancement and dosage lowering capability of cell‐targeted nanotherapy in the treatment of CVD.     

Delivery Techniques for Enhancing CAR T Cell Therapy against Solid Tumors

Chimeric antigen receptor (CAR) T cells exhibit promising results for cancer immunotherapy. However, the clinical success is still restricted to certain types of blood cancers, while in solid tumors the clinical activity is modest and potential toxicities remain a concern. There are various barriers that prevent CAR T cells from combating solid tumors. Therefore, distinct strategies have been explored to augment CAR T cell proliferative capacity, persistence, and effector function. Altering the tumor microenvironment, and in particular its physiochemical properties and immunosuppressive milieu, is of great significance to facilitate CAR T cell therapy. In this article, emerging strategies implemented to overcome the barriers of CAR T cell therapy in solid tumors are reviewed. Enhancing infiltration, activation, and persistence of CAR T cells has been addressed in several preclinical models. The future development of this field to promote innovation and clinical translation is also discussed.     

Negatively Charged Magnetite Nanoparticle Clusters as Efficient MRI Probes for Dendritic Cell Labeling and In Vivo Tracking

Cell labeling and tracking via magnetic resonance imaging (MRI) has drawn much attention for its noninvasive property and longitudinal monitoring functionality. Employing of imaging probes with high labeling efficiency and good biocompatibility is one of the essential factors that determine the outcome of tracking. In this study, negatively charged superparamagnetic iron oxide (PAsp‐PCL/SPIO) nanoclusters are developed for dendritic cell (DC) labeling and tracking in vivo. PAsp‐PCL/SPIO has a diameter of 124 ± 41 nm in DLS, negatively charged surface (zeta potential = ?27 mV), and presents high T ₂ relaxivity (335.6 Fe mm ^?1 s^?1) and good DC labeling efficiency. Labeled DCs are unaffected in their viability, proliferation, and differentiation capacity, and have an excellent MR imaging sensitivity in vitro. To monitor the migration of DCs into lymphoid tissues in vivo, which will be related to the final immunotherapy results, T ₂‐wighted and T ₂‐map imaging of popliteal nodes at different points in time are acquired under a clinical 3 T scanner after subcutaneous injection of a certain number of labeled DCs at hindleg footpads of mice. The signal intensities decreasing and T ₂ values shortening of ipsilateral popliteal nodes are significant and display a time‐ and dose‐dependence, showing DCs' migration to the draining lymph nodes.     

Cell-Based Delivery Systems: Emerging Carriers for Immunotherapy

Immunotherapy is leading a paradigm shift in the treatment of various diseases, including tumors, auto-immune diseases, and infectious diseases. However, the limited response rate and systemic side effects significantly impede the clinical applications of immunotherapy. As natural carriers for proteins and molecules, cells with low immunogenicity and toxicity have attracted considerable attention for biomedical applications and have achieved encouraging progress especially in immunotherapy. The convergence of multiple disciplines has equipped cell-based delivery systems with control over their spatiotemporal distribution to enhance treatment efficacy and reduce side effects. Here, an overview of the fundamentals and design principles of cell-based delivery systems followed by a perspective that includes the most recent advances of various cells as delivery carriers, with a special focus on the implications of cell-based delivery systems for immunotherapy is offered.     

Cationic Lipids-Mediated Dual-Targeting of Both Dendritic Cells and Tumor Cells for Potent Cancer Immunotherapy

Impaired antigen presentation either in dendritic cells (DCs) or tumor cells impedes the triggering of antitumor immunity or tumor cell killing, resulting in failures of multiple types of cancer immunotherapy. Herein, the strategy of using dual-targeting nanomedicines to simultaneously improve the presentation of tumor antigens by both DCs and tumor cells is proposed. It is shown that tuning of surface charge of nanoparticles (NPs) by incorporating different amounts of cationic lipids alters the in vivo NP tissue accumulation and cellular targeting profiles. NPs with moderately positive surface charge (≈20 mV) achieve efficient accumulation in tumors and lymph nodes and dual-targeting to both DCs and tumor cells. As a proof-of-concept demonstration, siRNA against YTH N6−methyladenosine RNA binding protein 1 (YTHDF1) is delivered by the dual-targeting NPs to inhibit excessive antigen degradation in both DCs and tumor cells. For DCs, YTHDF1 downregulation promotes tumor antigen cross-presentation and cross-priming of antigen-specific T cells. For tumor cells, it enhances the presentation of endogenous tumor antigens and hence improves both the recognition and killing of tumor cells by primed antigen-specific T cells. The dual-targeting nanomedicines generate efficient antitumor immunity.     

Photoporation with Biodegradable Polydopamine Nanosensitizers Enables Safe and Efficient Delivery of mRNA in Human T Cells

Safe and efficient production of chimeric antigen receptor (CAR)-T cells is of crucial importance for cell-based cancer immunotherapy. Physical transfection methods have quickly gained in importance in the context of transfecting T-cells, since they are readily compatible with different cell types and a broad variety of cargo molecules. In particular, nanoparticle-sensitized photoporation has been introduced in recent years as a gentle yet efficient method to transiently permeabilize cells, allowing subsequent entry of external cargo molecules into the cells. Gold nanoparticles (AuNPs) have been used the most as photothermal sensitizers because they can easily form laser-induced vapor nanobubbles, a photothermal phenomenon that is shown to be particularly efficient for permeabilizing cells. However, as AuNPs are not biodegradable, clinical translation is hampered. Here, for the first time, the possibility to form laser-induced vapor nanobubbles from biocompatible polymeric nanoparticles is reported. Compared to electroporation, the most used physical transfection method for T cells, 2.5 times more living mRNA transfected human T cells are obtained via photoporation sensitized by polydopamine nanoparticles. This shows that photoporation is a viable approach for efficiently producing therapeutic engineered T-cells at a throughput easily exceeding 10⁵ cells per second.     

ATM网信息元选择性丢失的分析

在ＡＴＭ网里信息元选择性丢（ＳＣＤ）是一个十分重要的问题。本文提出了一种两优先级ＳＣＤ方法，并对这种方法的性能在信息元离散时间到达的条件下进行了分析，克服了泊松到达假定的不足。通过引进π算子给出了一种能够加快收敛速度的计算信息元丢失概率的迭代算法。证明了ＳＣＤ方法在ＡＴＭ网中的有效性。     

Detecting the Origin of Cancer‐Mobile Quantum Probe for Single Cancer Stem Cell Detection

Cancer stem cells (CSC) are believed to be the driving force of cancer metastases and are a rare population of self‐renewing cells that contribute majorly to the poor outcomes of cancer therapy. The detection of CSC is of utmost importance to shed light on the indestructible nature of certain solid tumors and their metastatic ability. However, tumors tend to harbor CSCs in a specialized niche, making the detection process difficult. Currently, there is no method available to detect CSCs. The significance of this work is twofold. First, to the best of the knowledge, it is the first time that the detection of CSC is demonstrated. This approach simultaneously detects both the phenotypic and the metabolic state of the cell, thus enabling universal detection of CSC with high accuracy. Second, to the best of the knowledge, for the first time, light is shed on cell chemistry of CSC in their dedicated niche to facilitate a better understanding of the key players involved in the metabolic rewiring of CSC. This work will enable a better understanding of the fundamentals of CSCs, which are critical for the early diagnosis of cancer and the development of therapies for the cure of cancer.     

Transformable Nanoparticle‐Enabled Synergistic Elicitation and Promotion of Immunogenic Cell Death for Triple‐Negative Breast Cancer Immunotherapy

Although cisplatin‐based neoadjuvant chemotherapy is an efficient therapy approach for triple‐negative breast cancer (TNBC), it has dismal prognosis and modestly improved survival benefit. Here, a synergistic immunotherapy of TNBC premised on the elicitation and promotion of immunogenic cell death (ICD) response, through a transformable nanoparticle‐enabled approach for contemporaneous delivery of cisplatin, adjudin, and WKYMVm is reported. The nanoparticles can sequentially respond to matrix metalloproteinases‐2, pH, and glutathione to achieve structural transformation with the advantages of optimal size change, efficient drug delivery, and well‐controlled release. Cisplatin and adjudin can synergistically amplify reactive oxygen species (ROS) cascade and eventually increase the formation of hydrogen peroxide and downstream highly toxic ROS like ?OH, which can elicit ICD response by mechanisms of endoplasmic reticulum stress, apoptotic cell death, and autophagy. WKYMVm can further promote anti‐TNBC immunity by activation of formyl peptide receptor 1 to build stable interactions between dendritic cells and dying cancer cells. Thus, the nanoparticles achieve significant primary tumor regression and pulmonary metastasis inhibition as well as a remarkable survival benefit, with boosting of the innate and adaptive anti‐TNBC immunity.     

Selective Dispersion of Large‐Diameter Semiconducting Carbon Nanotubes by Functionalized Conjugated Dendritic Oligothiophenes for Use in Printed Thin Film Transistors

Selective dispersion of semiconducting single walled carbon nanotubes (s‐SWCNTs) by conjugated polymer wrapping is recognized as the most promising scalable method for s‐SWCNT separation. Despite a number of linear conjugated polymers being reported for use in s‐SWCNT separation, these linear polymers suffer batch‐to‐batch variation for their undefined molecular structure. Here, it is reported that conjugated dendritic oligothiophenes with multiple diketopyrrolopyrrole groups at the periphery have the capability of selectively dispersing large diameter s‐SWCNTs with high dispersion efficiency and certain chiral selectivity. Printed top‐gated thin film transistors using the dendrimer sorted s‐SWCNTs show high charge carrier mobility of up to 57 cm² V^?1 s^?1 and on/off ratios of ≈10⁶ with high reproducibility, which is ascribed to the defined and monodispersed molecular structure of dendrimers. Moreover, owing to the multiple peripheral anchoring groups of these dendritic molecules, these dendrimer‐s‐SWCNT dispersions display excellent stability. The current work proves that dendritic molecules are excellent dispersion reagents for s‐SWCNT separation.     

Drug-Eluting Shear-Thinning Hydrogel for the Delivery of Chemo- and Immunotherapeutic Agents for the Treatment of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a malignant and deadly form of liver cancer with limited treatment options. Transcatheter arterial chemoembolization, a procedure that delivers embolic and chemotherapeutic agents through blood vessels, is a promising cancer treatment strategy. However, it still faces limitations, such as inefficient agent delivery and the inability to address tumor-induced immunosuppression. Here, a drug-eluting shear-thinning hydrogel (DESTH) loaded with chemotherapeutic and immunotherapeutic agents in nanocomposite hydrogels composed of gelatin and nanoclays is presented as a therapeutic strategy for a catheter-based endovascular anticancer approach. DESTH is manually deliverable using a conventional needle and catheter. In addition, drug release studies show a sustained and pH-dependent co-delivery of the chemotherapy doxorubicin (acidic pH) and the immune-checkpoint inhibitor aPD-1 (neutral pH). In a mouse liver tumor model, the DESTH-based chemo/immunotherapy combination has the highest survival rate and smallest residual tumor size. Finally, immunofluorescence analysis confirms that DESTH application enhances cell death and increases intratumoral infiltration of cytotoxic T-cells. In conclusion, the results show that DESTH, which enables efficient ischemic tumor cell death and effective co-delivery of chemo- and immunotherapeutic agents, may have the potential to be an effective therapeutic modality in the treatment of HCC.     

Cancer Cell Membrane‐Coated Nanoparticles for Personalized Therapy in Patient‐Derived Xenograft Models

Cell membrane coating nanotechnology, which endows nanoparticles with unique properties, displays excellent translational potential in cancer diagnosis and therapy. However, the preparation and evaluation of these cell membrane‐coated nanoparticles are based on cell lines and cell‐line‐based xenograft mouse models. The feasibility of cell membrane‐camouflaged nanomaterials is tested in a preclinical setting. Head and neck squamous cell carcinoma (HNSCC) patient‐derived tumor cell (PDTC) membranes are coated onto gelatin nanoparticles (GNPs) and the resulting PDTC@GNPs show efficient targeting to homotypic tumor cells and tissues in patient‐derived xenograft (PDX) models. When the donor‐derived cell membrane of PDTC@GNPs matched those of the host cells, significant targeting capability is observed. In contrast, mismatch between the donor and host results in weak targeting. Furthermore, it is demonstrated that autologous separation and administration of cellular membranes and anticancer cisplatin (Pt)‐loaded PDTC@GNPs, respectively, lead to almost complete tumor ablation in a subcutaneous model and effectively inhibit tumor recurrence in a postsurgery model. The work presented here reinforces the translation of these biomimetic nanoparticles for clinical applications and offers a simple, safe, and effective strategy for personalized cancer treatment.     

A Smart DNA Nanoassembly Containing Multivalent Aptamers Enables Controlled Delivery of CRISPR/Cas9 for Cancer Immunotherapy

CRISPR/Cas9 system is promising for the reversal of tumor immunosuppression in immunotherapy, but the controlled delivery of CRISPR/Cas9 remains challenging. Herein, the study reported a smart DNA nanoassembly containing multivalent aptamers, realizing the controlled delivery of Cas9/sgRNA ribonucleoprotein (RNP) for enhanced cancer immunotherapy. A single-stranded DNA complementary to sgRNA in the Cas9/sgRNA RNP can initiate a cascade-clamped hybridization chain reaction (C-HCR) to wrap the Cas9/sgRNA RNP up in the DNA nanoassembly. After selective internalization of DNA nanoassembly by cancer cells, Cas9/sgRNA RNP is released to cytoplasm in response to endogenous RNase H and enters the nuclei to knock out β-catenin. The expression of the programmed death-ligand one gene is effectively suppressed, and the immunosuppressive tumor microenvironment is reprogrammed. Meanwhile, the migration of cancer cells is inhibited, and the apoptosis of cancer cells is promoted. In a breast cancer mouse model, the administration of DNA nanoassembly effectively increased the infiltration of CD8⁺ T cells, eventually achieving high therapeutic efficacy.     

Supramolecular Macrophage-Liposome Marriage for Cell-Hitchhiking Delivery and Immunotherapy of Acute Pneumonia and Melanoma

As many diseases are related to inflammation, the inflammatory tropism of immune cells may bring cell-hitchhikers directly to the disease tissues in a highly targeted manner. The current cell-hitchhiking strategies rely on either cellular internalization or covalent surface conjugation, which often affects the physiological function of transporting cells. Herein, a cell-friendly, host-guest chemistry mediated macrophage-liposome conjugate (M-L) is developed for extremely stable cell-hitchhiking drug delivery. M-L is prepared via simple supramolecular “hand-holding” and marriage between cucurbit[7]uril (CB[7]) and adamantane, respectively anchored on the surface of the macrophage and liposome, which demonstrates targeted accumulation in the inflamed lung and effective therapy of acute pneumonia in mice when loaded with quercetin. Upon loading toxic chemotherapeutic agents (such as doxorubicin and oxaliplatin), M-L carries the payloads to the inflammatory cancer tissue and significantly enhances the chemoimmunotherapy of melanoma in mice. Fundamentally, this CB[7]-based supramolecular M-L conjugation strategy shows negligible effects on the migratory and invasive behaviors of macrophages. In vivo pathological analysis of the inflammatory tissues in mice after treatment with M-L further suggests that macrophage and liposomes are delivered together hand in hand. This CB[7]-based, supramolecular cell-conjugation strategy potentially addresses the key challenges faced by the current cell-based delivery systems.     

Robust Prediction of Personalized Cell Recognition from a Cancer Population by a Dual Targeting Nanoparticle Library

Nanomaterials are used increasingly in diagnostics and therapeutics, particularly for malignancies. Efficient targeting of nanoparticles to specific cells is an important requirement for the development of successful nanoparticle‐based theranostics and personalized medicines. Gold nanoparticles are surface modified using a library of small organic molecules, and optionally folate, to investigate their ability to target four cell lines from common cancers, three having high levels of folate receptors expression. Uptake of these nanoparticles varies widely with surface chemistriy and cell lines. Sparse machine learning methods are used to computationally model surface chemistry–uptake relationships, to make quantitative predictions of uptake for new nanoparticle surface chemistries, and to elucidate molecular aspects of the interactions. The combination of combinatorial surface chemistry modification and machine learning models will facilitate the rapid development of targeted theranostics.     

A Gel‐Based Model of Selective Cell Motility: Implications for Cell Sorting,Diagnostics, and Screening

The ability to precisely control cell‐loaded material systems is essential for in vitro testing of novel therapeutics poised to advance to clinic. In this report, unique patterns of cell migration are devised into an in vitro gel‐in‐gel model for the purpose of obtaining cell response data to potentially therapeutic chemical agonists. The model consists of co‐cultures in a cell‐loaded microgel invading an acellular “sorting” gel. Material properties including biophysical and chemical compositions of the sorting gel are carefully controlled to guide a desired cell‐specific behavior, leading to massive tumor cell invasion by amoeboid migration mechanisms. Optical transparency enables straightforward and high‐throughput measurements of outgrowth response in the presence of either chemical and photoradiation therapy. Important dosing and drug sensitivity information are obtained with the gel‐in‐gel model using no more than a light microscope, without further need for arduous genomic or proteomic screening of the tissue samples.