Tumor Cell Membrane‐Coated Liquid Metal Nanovaccine for Tumor Preventionǂ

Herein, we report on a tumor nanovaccine LMNP@CM that enhances the process of antigen‐presenting by stimulating the immune system to uptake tumor antigens actively. The nanovaccine is comprised of polyethylene glycol modified liquid metal nanoparticles (LMNP) and tumor cell membranes (CM) as antigens. Under 808 nm irradiation, the photothermal conversion effect of injected LMNP can cause mild local inflammation, and subsequently induces antigen‐presenting cells active recruitment and facilitates cellular uptake of tumor antigens. Meanwhile, because of the immune adjuvant effect of metal materials, the nanovaccine LMNP@CM promotes the maturation and activation of antigen‐presenting cells and induces anti‐tumor immune response effectively. By priming the host immune recognition of tumor antigens, this nanovaccine displays prophylactic effects and significantly suppresses tumor growth in a mouse breast tumor model. The nanovaccine LMNP@CM represents a novel strategy of utilizing light‐controlled means to actively induce anti‐tumor immune processes, showing advanced therapeutic potentials and robust adaptability for treating multiple tumors by changing the loaded antigens.     

A tetrahedral framework nucleic acid based multifunctional nanocapsule for tumor prophylactic mRNA vaccination

Synthetic antigen-encoding mRNA plays an increasingly significant role in tumor vaccine technology owing to its antigen-specific immune-activation. However, its immune efficacy is challenged by inferior delivery efficiency and demand for suitable adjuvants. Here, we develop a novel mRNA nanovaccine based on a multifunctional nanocapsule, which is a dual-adjuvant formulation composed of cytosine-phosphate-guanine motifs loaded tetrahedral framework nucleic acid (CpG-tFNA) and an immunopeptide murine β-defensin 2 (mDF2β). This mRNA nanovaccine successfully achieves intracellular delivery, antigen expression and presentation of dendritic cells, and proliferation of antigen-specific T cells. In a tumor prophylactic vaccination model, it exerts an excellent inhibitory effect on lymphoma occurrence through cellular immunity. This mRNA nanovaccine has promising prophylactic applications in tumors and many other diseases.     

Sequential and Timely Combination of a Cancer Nanovaccine with Immune Checkpoint Blockade Effectively Inhibits Tumor Growth and Relapse

We describe a small lipid nanoparticle (SLNP)‐based nanovaccine platform and a new combination treatment regimen. Tumor antigen‐displaying, CpG adjuvant‐embedded SLNPs (OVA_PEP‐SLNP@CpG) were prepared from biocompatible phospholipids and a cationic cholesterol derivative. The resulting nanovaccine showed highly potent antitumor efficacy in both prophylactic and therapeutic E.G7 tumor models. However, this vaccine induced T cell exhaustion by elevating PD‐L1 expression, leading to tumor recurrence. Thus, the nanovaccine was combined with simultaneous anti‐PD‐1 antibody treatment, but the therapeutic efficacy of this regimen was comparable to that of the nanovaccine alone. Finally, mice that showed a good therapeutic response after the first cycle of immunization with the nanovaccine underwent a second cycle together with anti‐PD‐1 therapy, resulting in suppression of tumor relapse. This suggests that the antitumor efficacy of combinations of nanovaccines with immune checkpoint blockade therapy is dependent on treatment sequence and the timing of each modality.     

Non-covalent glycosylated gold nanoparticles/peptides nanovaccine as potential cancer vaccines

Herein, we firstly developed a non-covalent glycosylated gold nanoparticles/peptides nanovaccine which is assembled by β-cyclodextrin (β-CD) based host-guest recognitions. This nanovaccine can generate significant titers of antibodies and improve the therapeutic effect against melanoma, suggesting the immunogenicity of peptide antigens can be improved by loading with this carrier. The novel vaccine carrier provides a platform for the transport of various antigens especially T cell-independent antigens.     

Chiral resolution,absolute configuration determination,and stereo-activity relationship study of IDO1 inhibitor NLG919

NLG919 (1) with two chiral carbon atoms on its chemical structure is a potent indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor. We developed an effective way to prepare all stereoisomers of 1, the key step being the chiral resolution of racemic intermediate 2. The optimal resolution solvent system was identified as dichloromethane and n-pentane or petroleum ether. Using (?)-di-p-toluoyl-d-tartaric acid as resolution reagent, optical pure (R)-2 (e.e.?>?99%, yield?=?70%) was obtained. The mechanism of chiral resolution was clarified through single-crystal X-ray diffraction of the diastereomeric salt. The absolute configurations of four stereoisomers of 1 were established through electronic circular dichroism spectra, quantum chemical calculation and transition metal method. Their IDO1 inhibitory activity was assessed by pharmacological experiments in vitro and in mouse, demonstrating that S configuration of C5 played an important role on the inhibition of IDO1, while the stereochemistry on C2′ exerted little effect on the IDO1 inhibitory activity in mouse.     

Biointerface engineering of self-protective bionic nanomissiles for targeted synergistic chemotherapy

Erythrocyte membrane(EM)-camouflaged chemotherapeutic delivery nanovehicles hold promise for solid tumor therapy because of their excellent biostability and biocompatibility. However, it is accompanied with insufficient targeting effect and deficient pharmacokinetic behavior due to the lack of a regulated biointerface to navigate and overcome biological transportation obstacles in solid tumor therapy.Herein, an anti-epidermal growth factor receptor(EGFR) aptamer(EApt) modified and EM-cloaked che...     

2D graphene oxide-l-arginine-soybean lecithin nanogenerator for synergistic photothermal and NO gas therapy

Nitric oxide (NO) gas therapy has been regarded as a promising strategy for cancer treatment. However, its therapeutic efficiency is still unsatisfying due to the limitations of monotherapy. Previous preclinical and clinical studies have shown that combination therapy could significantly enhance therapeutic efficiency. Herein, a graphene oxide (GO)-l-arginine (l-Arg, a natural NO donor) hybrid nanogenerator is developed followed by surface functionalization of soybean lecithin (SL) for synergistic enhancement of cancer treatment through photothermal and gas therapy. The resultant GO-Arg-SL nanogenerator not only exhibited good biocompatibility and excellent endocytosis ability, but also exhibited excellent photothermal conversion capability and high sensitivity to release NO within tumor microenvironment via inducible NO synthase (iNOS) catalyzation. Moreover, the produced hyperthermia and intracellular NO could synergistically kill cancer cells both in vitro and in vivo. More importantly, this nanogenerator can efficiently eliminate tumor while inhibiting the tumor recurrence because of the immunogenic cell death (ICD) elicited by NIR laser-triggered hyperthermia and the immune response activation by massive NO generation. We envision that the GO-Arg-SL nanogenerator could provide a potential strategy for synergistic photothermal and gas therapy.     

Nanovaccines for cancer immunotherapy: Current knowledge and future perspectives

Cancer immunotherapy harnesses the immune system to attack tumors and has received extensive attention in recent years. Cancer vaccines as an important branch of immunotherapy are designed for delivering tumor antigens to antigen-presenting cells (APCs) to stimulate a strong immune response to against tumors, representing a potentially therapeutic and prophylactic effect with the long-term anti-cancer benefits. Nevertheless, the disappointing outcomes of their clinical use might be attributed to dilemma in antigen selection, immunogenicity, lymph nodes (LNs) targeting ability, lysosomal escape ability, immune evasion, etc. Nanotechnology, aiming to overcome these barriers, has been utilized in cancer vaccine development for decades. Numerous preclinical and clinical studies demonstrate positive results in nanomaterials-based cancer vaccines with considerable improvement in the vaccine efficacy. In this review, we systematically introduced the characteristics of nanovaccines and highlighted the different types of nanomaterials used for cancer vaccine design. In addition, the opportunities and challenges of the emerging nanotechnology-based cancer vaccines were discussed.     

Cordycepin Sensitizes Cholangiocarcinoma Cells to Be Killed by Natural Killer-92 (NK-92) Cells

Immunotherapy harnessing immune functions is a promising strategy for cancer treatment. Tumor sensitization is one approach to enhance tumor cell susceptibility to immune cell cytotoxicity that can be used in combination with immunotherapy to achieve therapeutic efficiency. Cordycepin, a bioactive compound that can be extracted from some Cordyceps spp. has been reported to effectively inhibit tumor growth, however, the mechanism of its tumor sensitization activity that enhances immune cell cytotoxicity is unknown. In the present study, we investigated the potency of cordycepin to sensitize a lethal cancer, cholangiocarcinoma (CCA), to natural killer (NK) cells. Treatment with cordycepin prior to and during co-culturing with NK-92 cells significantly increased cell death of KKU-213A as compared to solitary cordycepin or NK treatment. Moreover, sensitization activity was also observed in the combination of NK-92 cells and Cordyceps militaris extract that contained cordycepin as a major component. The cordycepin treatment remarkably caused an increase in TRAIL receptor (DR4 and DR5) expression in KKU-213A, suggesting the possible involvement of TRAIL signaling in KKU-213A sensitization to NK-92 cells. In conclusion, this is the first report on the sensitization activity of cordycepin on CCA cells to NK cytotoxicity, which supports that cordycepin can be further developed as an alternate immunomodulating agent.     

pIL-12 delivered by polymer based nanovector for anti-tumor genetherapy

Finding more effective and safe non-viral vectors to transfer genes into cancer cells has become the key of immune gene therapy for cancer. Herein a triblock compound MPEG₂₀₀₀–PDLLA₄₀₀₀–MPEG₂₀₀₀ modified by cationic liposome DOTAP was used as a non-viral vector DOTAP/MPEG₂₀₀₀–PDLLA₄₀₀₀–MPEG₂₀₀₀ (DMPM) to effectively transfer interleukin (IL)-12 plasmid (pIL-12) into tumor tissue. IL-12 produced by transfected tumor cells successfully inducing lymphocyte proliferation and promoting interferon-γ (IFN-γ) secretion, which resulted in tumor cells death. The ability of DMPM to transfer pIL-12 and the immune effect induced by IL-12 in cells had been explored. The anti-tumor effect, mechanism and safety of pIL-12/DMPM in mice cancer model were investigated in this study. Our results showed that the pIL-12 transferred by DMPM was highly expressed both in CT26 cells and B16-F10 cells. IL-12 expressed in the culture supernatant of transfected tumor cells stimulated lymphocyte proliferation and promoted IFN-γ secretion. The experimental result confirmed that pIL-12/DMPM therapy significantly reduced tumor growth in mice model. We designed the nanocomposite DMPM to deliver pIL-12 for cancer treatment and explored its therapeutic efficacy and the underlying anti-tumor mechanism. Our study suggested pIL-12 loaded by DMPM complex would be an effective strategy for cancer treatment.     

Mannose-Modified Multi-Walled Carbon Nanotubes as a Delivery Nanovector Optimizing the Antigen Presentation of Dendritic Cells

Dendritic cells (DCs) based cancer immunotherapy is largely dependent on adequate antigen delivery and efficient induction of DCs maturation to produce sufficient antigen presentation and ultimately lead to substantial activation of tumor-specific CD8⁺ T cells. Carbon nanotubes (CNTs) have attracted great attention in biomedicine because of their unique physicochemical properties. In order to effectively deliver tumor antigens to DCs and trigger a strong anti-tumor immune response, herein, a specific DCs target delivery system was assembled by using multi-walled carbon nanotubes modified with mannose which can specifically bind to the mannose receptor on DCs membrane. Ovalbumin (OVA) as a model antigen, could be adsorbed on the surface of mannose modified multi-walled carbon nanotubes (Man-MWCNTs) with a large drug loading content. This nanotube-antigen complex showed low cytotoxicity to DCs and was efficiently engulfed by DCs to induce DCs maturation and cytokine release in vitro, indicating that it could be a potent antigen-adjuvant nanovector of efficient antigen delivery for therapeutic purpose.     

ICG@ZIF-8: One-step encapsulation of indocyanine green in ZIF-8 and use as a therapeutic nanoplatform

This work reported a one-step encapsulation of indocyanine green (ICG) in ZIF-8 nanoparticles (NPs), which possess an absorption band in the near infrared region and have the good photothermal conversion efficiency. The in vivo and in vitro studies show that, after loading DOX, ICG@ZIF-8-DOX NPs exhibit the chem-band photothermal synergistic therapy for tumor.     

MnOx Nanospikes as Nanoadjuvants and Immunogenic Cell Death Drugs with Enhanced Antitumor Immunity and Antimetastatic Effect

Despite the widespread applications of manganese oxide nanomaterials (MONs) in biomedicine, the intrinsic immunogenicity of MONs is still unclear. MnO_x nanospikes (NSs) as tumor microenvironment (TME)‐responsive nanoadjuvants and immunogenic cell death (ICD) drugs are proposed for cancer nanovaccine‐based immunotherapy. MnO_x NSs with large mesoporous structures show ultrahigh loading efficiencies for ovalbumin and tumor cell fragment. The combination of ICD via chemodynamic therapy and ferroptosis inductions, as well as antigen stimulations, presents a better synergistic immunopotentiation action. Furthermore, the obtained nanovaccines achieve TME‐responsive magnetic resonance/photoacoustic dual‐mode imaging contrasts, while effectively inhibiting primary/distal tumor growth and tumor metastasis.     

Programmed polymersomes with spatio-temporal delivery of antigen and dual-adjuvants for efficient dendritic cells-based cancer immunotherapy

Since antigen and adjuvant are rapid clearance in vivo, insufficient delivery to induce dendritic cells (DCs) maturation and cross-presentation, as well as limited migration efficiency of DCs to secondary lymph organs, greatly hinders the development of DCs-based immunotherapy. Herein, PCL-PEG-PCL polymersomes (PCEP-PS) as antigen and adjuvants delivery nanoplatforms (IMO-PS) were well-designed, which can electrostatically adsorb OVA antigen on the surface via DOTAP lipid and effectively encapsulate OVA antigen into the inner hydrophilic cavity to achieve both initial antigen exposure as well as slow and sustained antigen release, incorporate MPLA within the lipid layer to ligate with extracellular TLR4 of DCs as well as encapsulate IMQ in the hydrophobic membrane to ligate with intracellular TLR7/8 of DCs for activating synergistic immune responses via different signaling pathways. The IMO-PS significantly improved antigen uptake, promoted DCs maturation and cytokines production. DCs treated with IMO-PS could enhance migration into draining lymphoid nodes, and eventually induced antigen-specific CD8⁺ and CD4⁺ T cell responses and OVA-specific cytotoxic T lymphocyte (CTL) responses. Prophylactic vaccination of EG7-OVA tumor-bearing mice by IMO-PS + DCs significantly extended tumor-free time, effectively suppressed tumor growth, and greatly extended median survival time. The strategy may provide an effective nanoplatform for co-delivery antigen and dual-adjuvants in a spatio-temporally programmed manner for DC-based cancer immunotherapy.     

Radiotherapy assisted with biomaterials to trigger antitumor immunity

As an extensively applied therapeutic approach to combat tumors, radiotherapy generates localized ionizing radiation to destruct tumor cells. Despite its importance in clinical oncology, radiotherapy would often cause significant organ toxicity, and its therapeutic effect is limited by tumor hypoxia. Moreover, although abscopal therapeutic effects have occasionally been observed, radiotherapy is still mostly employed as a local treatment method that could hardly control tumor metastases. In recent years, strategies involving biomaterials and nanomedicine have received increasingly high attention to enhance cancer radiotherapy. Beyond sensitizing tumors for radiotherapy via various mechanisms, many biomaterial systems with immune stimulating effects have also been introduced to boost the antitumor immunity post cancer radiotherapy. In this mini-review, we will summarize the progress of different biomaterials and nanomedicine systems in combination with radiotherapy to trigger antitumor immune responses and enhance the efficacy of immunotherapy, and discusses the perspectives and challenges of this research direction aimed at clinical translations.     

Black phosphorus nanosheets-based tumor microenvironment responsive multifunctional nanosystem for highly efficient photo-/sono-synergistic therapy of non-Hodgkin lymphoma

Finding improved therapeutic protocols against non-Hodgkin's lymphoma (NHL) remains an unmet clinical demand. Phototherapy is a promising alternative treatment for traditional clinical therapeutic methods, but the limited tissue penetration blocks the therapeutics. Inspired by the excellent physical and chemical properties of black phosphorus nanosheets (BPNSs), a fluorescence and thermal imaging guided photo-/sono-synergistic treatment platform BPNSs@PEG-SS-IR780/RGD is developed. This ingenious multifunctional theranostic platform not only exhibits outstanding photothermal conversion efficiency and highly efficient reactive oxygen species generation, but also has good biocompatibility, tumor-targeting and tumor microenvironment responsiveness. In addition, BPNSs@PEG-SS-IR780/RGD could actively target the tumor sites and generate excellent photothermal, photodynamic and sonodynamic therapeutic efficacy. Both in vitro and in vivo experiments indicate that BPNSs@PEG-SS-IR780/RGD can be a promising nanomaterial for NHL imaging and therapy. Taken together, this study not only expands the application field of black phosphorus materials, but also provides a possibility to design a new generation of NHL treatment regimens with clinical application potential.     

Porphyrin Nanocage‐Embedded Single‐Molecular Nanoparticles for Cancer Nanotheranostics

Single molecular nanoparticles (SMNPs) integrating imaging and therapeutic capabilities exhibit unparalleled advantages in cancer theranostics, ranging from excellent biocompatibility, high stability, prolonged blood lifetime to abundant tumor accumulation. Herein, we synthesize a sophisticated porphyrin nanocage that is further functionalized with twelve polyethylene glycol arms to prepare SMNPs ( porSMNPs ). The porphyrin nanocage embedded in porSMNPs can be utilized as a theranostic platform. PET imaging allows dynamic observation of the bio‐distribution of porSMNPs , confirming their excellent circulation time and preferential accumulation at the tumor site, which is attributed to the enhanced permeability and retention effect. Moreover, the cage structure significantly promotes the photosensitizing effect of porSMNs by inhibiting the π–π stacking interactions of the photosensitizers, ablating of the tumors without relapse by taking advantage of photodynamic therapy.     

Smart Nanosensitizers for Activatable Sono-Photodynamic Immunotherapy of Tumors by Redox-Controlled Disassembly

Tumor-targeted and stimuli-activatable nanosensitizers are highly desirable for cancer theranostics. However, designing smart nanosensitizers with multiple imaging signals and synergistic therapeutic activities switched on is challenging. Herein, we report tumor-targeted and redox-activatable nanosensitizers ( 1-NPs ) for sono-photodynamic immunotherapy of tumors by molecular co-assembly and redox-controlled disassembly. 1-NPs show a high longitudinal relaxivity (r₁=18.7±0.3 mM⁻¹ s⁻¹), but “off” dual fluorescence (FL) emission (at 547 and 672 nm), “off” sono-photodynamic therapy and indoleamine 2,3-dioxygenase 1 (IDO1) inhibition activities. Upon reduction by glutathione (GSH), 1-NPs rapidly disassemble and remotely release small molecules 2-Gd , Zn-PPA-SH and NLG919, concurrently switching on (1) dual FL emission, (2) sono-photodynamic therapy and (3) IDO1 inhibition activities. After systemic injection, 1-NPs are effective for bimodal FL and magnetic resonance (MR) imaging-guided sono-photodynamic immunotherapy of orthotropic breast and brain tumors in mice under combined ultrasound (US) and 671-nm laser irradiation.     

Alum colloid encapsulated inside β-glucan particles enhance humoral and CTL immune responses of MUC1 vaccine

We have developed a MUC1 antigen-based antitumor vaccine loaded on alum colloid encapsulated insideβ-glucan particles(GP-Al). The constructed vaccine induced strong MUC1 antigen specific Ig G antibody titers and enhanced CD8~+ T cells cytotoxic effect to kill tumor cells. These results indicated that GP-Al can be served as an efficient delivery system and adjuvant for the development of cancer vaccines especially small molecule antigens based cancer vaccines.