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.     

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.     

Artificial Immunogenic Cell Death Lipid Nanoparticle Functions as a Therapeutic Vaccine for Cancer

Anticancer drug-mediated induction of immunogenic cell death (ICD) blocks metastasis or recurrence in cancer cells by promoting specific immune activity against cancer antigens. However, this strategy has failed to afford adequate treatment efficiency. Overcoming the failure of ICD-mediated cancer therapy, lipid nanoparticles (LNPs) containing cancer cell surface proteins are synthesized using sonication and extrusion without microfluidics. In addition, these LNPs are decorated with high-mobility group box 1 protein and calreticulin, indicators of ICD, and named artificial ICD LNPs (AiLNPs). Administration of AiLNPs effectively targets dendritic cells (DCs) and induces DC activation in mice. Moreover, treating CT-26 tumor-bearing mice with AiLNPs inhibits tumor growth by inducing CT-26 antigen-specific T-cell immunity. Furthermore, AiLNPs containing Lewis lung carcinoma (LLC1) membrane proteins can prevent metastatic LLC1 tumor growth in the lung via LLC1 antigen-specific T-cell activation. Finally, AiLNPs synthesized with human breast cancer membrane proteins activate DC-mediated antigen-specific T-cell immunity, effectively killing tumor cells. Therefore, AiLNPs are expected to be developed as a patient-specific cancer treatment to prevent cancer recurrence and metastasis.     

Nanomedicine-Boosting Tumor Immunogenicity for Enhanced Immunotherapy

Immunotherapy has revolutionized oncology remarkably and gained great improvements in cancer therapy. However, tumor immunotherapy still encounters serious challenges, especially certain tumors barely respond to immunotherapy. The lack of immunogenicity and subsequent insufficient antitumor immune activation is a pivotal reason. Here, a general introduction and the strengthening strategies of immunogenicity of a tumor for enhanced immunotherapy are reviewed. Specifically, nanotechnology nowadays is playing important roles in increasing the antitumor efficacy of various treatments, including immunotherapy. This review highlights how nanomedicines integrating one or more anticancer therapeutic methods (e.g., cancer vaccines, chemotherapy, phototherapy, and radiotherapy) to increase the tumor immunogenicity for rousing T cell related immune responses and achieving inspiring antitumor efficacy. Given the sophisticated immune evasion mechanisms, rational designed nanodrugs with combinational formulations are summarized to improve therapeutic efficacy in synergistic ways. Nanoplatforms taking advantage of the distinct features of tumor tissue or tumor cell with stimuli-responsiveness and targeting functions are introduced to accelerate tumor accumulation of drugs successfully and greatly promote therapeutic efficacy with low-dose administration and programmed drug release. Finally, the related challenges and personal perspectives of nanomedicines for tumor immunotherapy are concluded.     

Reshaping Antitumor Immunity with Chemo-Photothermal Integrated Nanoplatform to Augment Checkpoint Blockade-Based Cancer Therapy

Immune checkpoint therapy promotes cytotoxic T lymphocytes (CTLs) activity to eliminate tumors. Nevertheless, their effectiveness in solid tumors is limited by inadequate infiltration of CTLs and suppressive tumor microenvironment (TME). Herein, an anti-PD-1 antibody coupled chemo-photothermal integrated nanoplatform (A/Au@MSMs-P) is proposed to reshape antitumor immunity against cancer. The matrix metalloproteinase-2 (MMP-2) responsive A/Au@MSMs-P promotes the separation of abemaciclib-loaded gold-silica nanoparticles (A/Au@MSMs) and anti-PD-1 antibody, achieving a triple-coordinated strategy to enhance checkpoint blockade therapy. First, chemo-photothermal therapy of A/Au@MSMs induces cell cycle arrest in G1 phase and promotes tumor cells apoptosis to achieve local ablation. Second, immunogenic death of tumor cells promotes the maturation of dendritic cells and recruits antigen-specific CTLs into tumor tissue to promote immune activation. Third, abemaciclib markedly suppresses the proliferation of regulatory T cells (Tregs) to alleviate the immunosuppression of the TME and potentiates the effectiveness of CTLs. This triple-coordinated strategy not only reshapes the antitumor immunity to enhance checkpoint blockade, but also cooperates with chemo-photothermal therapy, leading to improved antitumor efficiency and prolonged survival rate. Taken together, this study presents a promising strategy for improving checkpoint therapy response and has great potential in future cancer therapy.     

pH/Cathepsin B Hierarchical‐Responsive Nanoconjugates for Enhanced Tumor Penetration and Chemo‐Immunotherapy

An ideal cancer nanomedicine should precisely deliver therapeutics to its intracellular target within tumor cells. However, the multiple biological barriers seriously hinder their delivery efficiency, leading to unsatisfactory therapeutic outcome. Herein, pH/cathepsin B hierarchical‐responsive nanoconjugates (HRNs) are reported to overcome these barriers by sequentially responding to extra‐ and intracellular stimuli in solid tumors for programmed delivery of docetaxel (DTX). The HRNs have stable nanostructures (≈40 nm) in blood circulation for efficient tumor accumulation, while the tumor extracellular acidity induces the rapid dissociation of HRNs into polymer conjugates (≈5 nm), facilitating the deep tumor penetration and cellular internalization. After being trapped into the lysosomes, the conjugates are cleaved by cathepsin B to release bioactive DTX into cytoplasm and inhibit cell proliferation. In addition to the direct inhibition effect, HRNs can trigger the in vivo antitumor immune responses via the immunogenic modulation of tumor cells, activation of dendritic cells (DCs), and generation of cytotoxic T‐cell responses. By employing a combination with α‐PD‐1 (programmed cell death 1) therapy, synergistic antitumor efficacy is achieved in B16 expressing ovalbumin (B16OVA) tumor model. Hence, this strategy demonstrates high efficiency for precise intracellular delivery of chemotherapeutics and provides a potential clinical candidate for cancer chemo‐immunotherapy.     

Screening of Zwitterionic Liposomes with Red Blood Cell-Hitchhiking and Tumor Cell-Active Transporting Capability for Efficient Tumor Entrance

The active transport of nanoparticles into the solid tumor through cell transcytosis has shown great promise in cancer nanomedicine, but it is challenging to develop efficient active transporting nanomedicines with the potential for clinical translation. Here, a type of tertiary amine oxide (TAO)-containing zwitterionic liposomal nanocarriers is developed that can hitchhike red blood cells (RBCs) to tumor blood vessels and enter solid tumors through transcytosis. To boost the active-transporting capability, a library of the TAO liposomes (TAOLs) with different chemical structures and particle sizes is constructed and screened by their stability and active transporting capability. Two types of TAOLs are identified that can induce efficient tumor cell transcytosis through rapid macropinocytosis and endoplasmic reticulum/Golgi-involved exocytosis. It is found that these zwitterionic TAOLs can hitchhike RBCs to gain long blood circulation, get off the cell at the tumor site, effectively enter the tumor through transcytosis, and infiltrate the whole tumor. The chemotherapeutic drug-loaded liposomes can stop the tumor progression of mice bearing human hepatocellular carcinoma HepG2 cells, exhibiting superior antitumor activity compared to the traditional liposomal drug. This study demonstrates a strategy to construct effective active transporting liposomal nanomedicines for efficient tumor entrance.     

Stabilizing RNA Nanovaccines with Transformable Hyaluronan Dynamic Hydrogel for Durable Cancer Immunotherapy

Massage RNA (mRNA) vaccines represent a new strategy for advanced cancer immunotherapy. To protect mRNA from degradation and deliver to targeted cells, lipid nanoparticles (LNPs) are extensively utilized as non-viral vectors. However, the stability of mRNA-laden LNPs substantially hinders their clinical application. Development of thermostable and durable mRNA nanovaccines is urgently needed. Here, a hyaluronan dynamic hydrogel is reported to protect mRNA and resiquimod (R848)-laden LNPs (HA-mRLNPs) from degradation at room temperature for durable cancer immunotherapy. A microfluidic device is proposed to effectively encapsulate mRNA and immunoadjuvants in LNPs (mRLNPs). Then, hyaluronan dynamic hydrogel is used to stabilize LNPs during storage at room temperature by restricting the migration and fusion of LNPs. Particularly, gel-like hyaluronan undergoes state transition for controlled release of mRLNPs under physiological condition. Therefore, HA-mRLNPs can efficiently deliver mRNA encoding tumor antigens to dendritic cells for antigen presentation to induce antigen-specific CD8⁺ T cells for killing tumor cells. Overall, this study demonstrates that the LNPs-hydrogel system can be used for effective cancer immunotherapy.     

Nanovaccine-Mediated Cell Selective Delivery of Neoantigens Potentiating Adoptive Dendritic Cell Transfer for Personalized Immunization

Neoantigen vaccines and adoptive dendritic cell (DC) transfer are major clinical approaches to initiate personalized immunity in cancer patients. However, the immunization efficacy is largely limited by the in vivo trajectory including neoantigens’ access to resident DCs and DCs’ access to lymph nodes (LNs). Herein, an innovative strategy is proposed to improve personalized immunization through neoantigen-loaded nanovaccines synergized with adoptive DC transfer. It is found that it enables selective delivery of neoantigens to resident DCs and macrophages by coating cancer cell membranes onto neoantigen-loaded nanoparticles. In addition, the nanovaccines promote the secretion of chemokine C-C motif ligand 2 (CCL2), CCL3, and C-X-C motif ligand 10 from macrophages, thus potentiating the access of transferred DCs to LNs. This immunization strategy enables coordinated delivery of identified neoantigens and autologous tumor lysate-derived undefined antigens, leading to initiation of antitumor T cell immunity in a personalized manner. It significantly inhibits tumor growth in prophylactic and established mouse tumor models. The findings provide a new vision for potentiating adoptive cell transfer by nanovaccines, which may open the door to a transformative possibility for improving personalized immunization.     

Enhanced Charge Separation Efficiency in DNA Templated Polymer Solar Cells

The insertion of a DNA nanolayer into polymer based solar cells, between the electron transport layer (ETL) and the active material, is proposed to improve the charge separation efficiency. Complete bulk heterojunction donor–acceptor solar cells of the layered type glass/electrode (indium tin oxide)/ETL/P3HT:PC₇₀BM/hole transport layer/electrode (Ag) are investigated using femtosecond transient absorption spectroscopy both in the NIR and the UV–vis regions of the spectrum. The transient spectral changes indicate that when the DNA is deposited on the ZnO nanoparticles (ZnO‐NPs) it can imprint a different long range order on the poly(3‐hexylthiophene) (P3HT) polymer with respect to the non‐ZnO‐NPs/DNA containing cells. This leads to a larger delocalization of the initially formed exciton and its faster quenching which is attributed to more efficient exciton dissociation. Finally, the temporal response of the NIR absorption shows that the DNA promotes more efficient production of charge transfer states and free polarons in the P3HT cation indicating that the increased exciton dissociation correlates with increased charge separation.     

Synergy of Immunostimulatory Genetherapy with Immune Checkpoint Blockade Motivates Immune Response to Eliminate Cancer

Normalizing the tumor-induced immune deficiency in the immunosuppressive tumor microenvironment (TME) through increasing the efficient infiltration and activation of antitumoral immunity in TME is the core of promising immunotherapy. Herein, a Cyclo(Arg-Gly-Asp-d -Phe-Lys) (RGD) peptides-modified combinatorial immunotherapy system based on the self-assembly of the nanoparticles named RGD-DMA composed of RGD-PEG-PLA, methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) and 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP) is used to codeliver the immunostimulatory chemokine CCL19-encoding plasmid DNA (CCL19 pDNA) and immune checkpoint ligand PD-L1 inhibitor (BMS-1). The RGD-DMA/pCCL19-BMS-1 system not only exhibited significant inhibition of tumor progression but also induced locally high concentrations of immunostimulatory cytokines at tumor sites without causing an obviously systemic inflammatory response. The immunosuppressive TME is efficaciously reshaped by the coadministration of RGD-DMA/pCCL19 and BMS-1, as indicated by the activated T lymphocytes, increased intratumoral-infiltration of mature dendritic cells (DCs), and the repolarization of macrophages from pro-tumoral M2-phenotype toward tumoricidal M1-phenotype. The upregulated PD-L1 expression at tumor sites caused by the increased IFN-γ levels after immunostimulatory gene therapy further demonstrated the synergistic effects of BMS-1 in counteracting the inhibitory role of PD-L1 expression in antitumor immunity. Therefore, the combination of immunostimulating therapy and immune checkpoint inhibitor that synergistically target multiple immune regulatory pathways demonstrates significant potential as a novel immunotherapy approach.     

iRGD Modified Chemo‐immunotherapeutic Nanoparticles for Enhanced Immunotherapy against Glioblastoma

Glioblastoma is the most common primary brain tumor in adults and still remains incurable, due to the limited accumulation of drugs in the tumor area. Herein, iRGD‐modified nanoparticles, DOX@MSN‐SS‐iRGD&1MT, are developed for simultaneous delivery of chemotherapeutic agents (doxorubicin, DOX) and immune checkpoint inhibitor (1‐methyltryptophan, 1MT) into orthotopic glioma. The nanoparticles are comprised of mesoporous silica nanoparticles loaded with DOX, combined with Asp‐Glu‐Val‐Asp (DEVD) connected 1MT, and finally modified by iRGD. These nanoparticles show the capability of penetrating through blood brain barrier into the tumor area, and significantly improve accumulation of drugs in orthotopic brain tumors with minimal side effects. The nanoparticles also activate cytotoxic CD8⁺ T lymphocytes and inhibit CD4⁺ T cells in both GL261 cells cocultured with splenocytes in vitro and GL261‐luc orthotopic tumors in vivo. Moreover, the expression of antitumor cytokines IFNα/β, IFN‐γ, TNF, IL‐17, STING, and GrzB is upregulated while protumor proteins p‐STAT3 and IL‐10 are downregulated in the brain tumor area. This study demonstrates the advantages of chemo‐immunotherapeutic nanoparticles accumulated in the brain tumor area and their effectively inhibiting tumor proliferation, which establishes a delivery platform to promote antitumor immunity against glioblastoma.     

Ultrasonic Cavitation-Assisted and Acid-Activated Transcytosis of Liposomes for Universal Active Tumor Penetration

Active tumor penetration has been recently recognized as a promising strategy to resolve the limitation of nanomedicine in terms of tumor penetration, but it is challenging to develop active transporting nanocarriers. Here, an ultrasonic cavitation-assisted and acid-activatable active transporting liposome for a broad range of tumors is reported. The active transporting liposome (size and charge dual-conversional gemcitabine prodrug-integrated liposomal nanodroplet (SCGLN)) overcomes the tight blood vessel walls with the aid of ultrasonic cavitation. The SCGLN subsequently transforms from micro-size to nano-size under prolonged ultrasound radiation. Once in the acidic tumor microenvironment, the nanosized SCGLN undergoes negative-to-positive charge-reversal and triggers the cationization-initiated transcytosis to penetrate deep into tumor parenchyma. The gemcitabine-loaded SCGLN exhibits potent antitumor activity in multiple poorly permeable tumor models, which completely erases subcutaneous U251 glioma and stops the progression of orthotopic BxPC3 pancreatic ductal adenocarcinoma. This study presents a promising and universal strategy to develop active penetrating nanomedicines for efficient drug delivery in the low permeable tumor.     

Acidity‐Triggered Tumor‐Targeted Chimeric Peptide for Enhanced Intra‐Nuclear Photodynamic Therapy

Photodynamic therapy suffers from poor tumor selectivity and poor therapeutical efficacy. In this paper, an amphiphilic chimeric peptide is fabricated to realize sequential acidity‐responsive tumor‐targeted transport of photosensitizer and in situ photodynamic therapy in nuclei. In vitro studies demonstrate that the acidic tumor microenvironment successfully sheds the mask of cationic nuclear localization sequence (NLS) of the negatively charged chimeric peptide. This charge reversal remarkably accelerates cellular uptake of chimeric peptide in tumor cells and maximizes the photodynamic therapeutical efficacy in nuclei. Most importantly, direct disguise of the biofunctional NLS sequence decreases the complexity and increases the performance of the chimeric peptide further by achieving long blood retention time, specific tumor accumulation, minimal side effects, and efficient antitumor therapy in vivo.     

Oxygen-Generating Cryogels Restore T Cell Mediated Cytotoxicity in Hypoxic Tumors

Solid tumors are protected from antitumor immune responses due to their hypoxic microenvironments. Weakening hypoxia-driven immunosuppression by hyperoxic breathing of 60% oxygen has shown to be effective in unleashing antitumor immune cells against solid tumors. However, efficacy of systemic oxygenation is limited against solid tumors outside of lungs and has been associated with unwanted side effects. As a result, it is essential to develop targeted oxygenation alternatives to weaken tumor hypoxia as novel approaches to restore immune responses against cancer. Herein, injectable oxygen-generating cryogels (O₂-cryogels) to reverse tumor-induced hypoxia are reported. These macroporous biomaterials are designed to locally deliver oxygen, inhibit the expression of hypoxia-inducible genes in hypoxic melanoma cells, and reduce the accumulation of immunosuppressive extracellular adenosine. The data show that O₂-cryogels enhance T cell-mediated secretion of cytotoxic proteins, restoring the killing ability of tumor-specific cytotoxic T lymphocytes, both in vitro and in vivo. In summary, O₂-cryogels provide a unique and safe platform to supply oxygen as a coadjuvant in hypoxic tumors and have the potential to improve cancer immunotherapies.     

Multiantigenic Nanoformulations Activate Anticancer Immunity Depending on Size

Nanoparticle‐adjuvanted cancer vaccines are attracting increasing attention because they can induce an effective anticancer immune response. Single‐antigen vaccines are inefficient to inhibit cancer progression due to the heterogeneity of tumors and the antigenicity alteration of tumor‐associated antigens. Therefore, the efficient delivery of multiple antigens to antigen‐presenting cells is an excellent opportunity for strong anticancer immunity. In this study, three immunoadjuvant‐loaded multiantigenic nanoparticles MANPs/R837 with different diameters, i.e., 83, 103, and 122 nm, are prepared through coating of the cancer cell membrane as a source of multiple antigens onto the imiquimod R837‐loaded poly(lactic‐co‐glycolic acid) nanoparticles. The MANP/R837 with a diameter of 83 nm (MANP83/R837) shows the most efficient delivery of the payload to the draining lymph nodes and achieves the best antigen presentation to T lymphocytes. Compared with the other two nanovaccines, MANP83/R837 has a stronger inhibitory effect on tumor growth and metastasis. In the combination therapy with checkpoint blockade therapy using programmed cell death‐1 antibody, MANPs/R837 show effective inhibition against tumor progression, and MANP83/R837 achieves the most exciting effect. Therefore, MANPs/R837, as a promising therapeutic cancer vaccine, demonstrates great prospects in cancer immunotherapy.     

Triphenylphosphonium‐Conjugated Poly(ε‐caprolactone)‐Based Self‐Assembled Nanostructures as Nanosized Drugs and Drug Delivery Carriers for Mitochondria‐Targeting Synergistic Anticancer Drug Delivery

For mitochondria‐targeting delivery, a coupling reaction between poly(ε‐caprolactone) diol (PCL diol) and 4‐carboxybutyltriphenylphosphonium (4‐carboxybutyl TPP) results in the synthesis of amphiphilic TPP‐PCL‐TPP (TPCL) polymers with a bola‐like structure. In aqueous environments, the TPCL polymer self‐assembled via cosolvent dispersion and film hydration, resulting in the formation of cationic nanoparticles (NPs) less than 50 nm in size with zeta‐potentials of approximately 40 mV. Interestingly, different preparation methods for TPCL NPs result in various morphologies such as nanovesicles, nanofibers, and nanosheets. In vitro cytotoxicity results with TPCL NPs indicate IC₅₀ values of approximately 10–60 μg mL^?1, suggesting their potential as anticancer nanodrugs. TPCL NPs can be loaded both with hydrophobic doxorubicin (Dox) and its hydrophilic salt form (Dox·HCl), and their drug loading contents are approximately 2–10 wt% depending on the loading method and the hydrophilicity/hydrophobicity of the drugs. Although Dox·HCl exhibits more cellular and nuclear uptake, resulting in greater antitumor effects than Dox, most drug‐loaded TPCL NPs exhibit higher mitochondrial uptake and approximately 2–7‐fold higher mitochondria‐to‐nucleus preference than free drugs, resulting in superior (approximately 7.5–18‐fold) tumor‐killing activity for most drug‐loaded TPCL NPs compared with free drugs. In conclusion, TPCL‐based nanoparticles have potential both as antitumor nanodrugs themselves and as nanocarriers for chemical therapeutics.     

Different antitumor immunity roles of cytokine activated T lymphocytes from naive murine splenocytes and from dendritic cells-based vaccine primed splenocytes: implications for adoptive immunotherapy

AIM: The aim of the study is to explore the antitumor capacity of effector cells generated from murine splenocytes with sequential addition of a cocktail of cytokines and the possible contribution of dendritic cells to the antitumor capacity of these effector cells. METHODS AND RESULTS: Interferon-gamma, interleukin (IL)-1 beta, anti-CD3 mAb and IL-2 were used to activate murine splenocytes either from naive mice (termed cytokine activated T cells, CAT) or from DC based vaccine primed mice (termed specific effector T cells, SET). The antitumor roles of SET and CAT were analyzed in murine L615 T lymphocytic leukemia. Both CAT and SET were CD4(+)-predominant phenotypically and didn't show any significant cytotoxicity against a variety of syngeneic and allogeneic target cell lines using 51Cr release assay. When injected in vivo in combination with CY, CAT can cure a large proportion of leukemia mice. The cured mice couldn't establish specific antitumor immunity. However, in contrast to the roles of CAT, SET show far superior antitumor efficacy on a per cell basis compared with CAT. Moreover, the SET cured mice developed tumor specific long term memory immunity which was sufficient to reject a subsequent otherwise lethal tumor cells rechallenge and was transferable to naive immunocompetent mice. CONCLUSION: Our data demonstrate that there remain fundamentally different antitumor functions of CAT and SET which might be useful in the immunotherapy strategy choices.     

Metformin Mediated PD-L1 Downregulation in Combination with Photodynamic-Immunotherapy for Treatment of Breast Cancer

Intelligent nanomaterials open up new avenues for realizing safer and more effective combination immunotherapy. Herein, a kind of simple enzymatically cleavable self-delivery nanoparticles (MA-pepA-Ce6 NPs) is developed by conjugating acidic-sensitive small-molecule programmed cell death ligand 1 (PD-L1) inhibitor (Metformin, MET) with photosensitizer (chlorin e6, Ce6) through matrix metalloproteinase-2 (MMP-2) cleavable peptide (GPLGVRGDK, pepA). Noticeably, these self-delivery peptide-based NPs can circumvent the controversial biosafety facing nanomaterials. Moreover, MA-pepA-Ce6 NPs are degraded by overexpressed MMP-2 in tumor microenvironment (TME) and expose the VRGDK-Ce6. The exposed VRGDK-Ce6 shows superior targeting ability towards integrin α_vβ₃ receptor, ensuring sufficient accumulation and laser-activated robust antitumor immune effects. Remarkably, the released MET in tumor microenvironment hampers the PD-L1 expression and augments the antitumor immune response elicited by photodynamics therapy (PDT), thus significantly improving therapeutic outcomes. Overall, this study offers a potential appealing paradigm of synergistic PDT-triggered immunotherapy by revealing MET-mediated PD-L1 downregulation to achieve tumor eradication.     

Plasmonic Electrically Functionalized TiO2 for High‐Performance Organic Solar Cells

Optical effects of the plasmonic structures and the materials effects of the metal nanomaterials have recently been individually studied for enhancing performance of organic solar cells (OSCs). Here, the effects of plasmonically induced carrier generation and enhanced carrier extraction of the carrier transport layer (i.e., plasmonic‐electrical effects) in OSCs are investigated. Enhanced charge extraction in TiO₂ as a highly efficient electron transport layer by the incorporation of metal nanoparticles (NPs) is proposed and demonstrated. Efficient device performance is demonstrated by using Au NPs incorporated TiO₂ at a plasmonic wavelength (560–600 nm), which is far longer than the originally necessary UV light. By optimizing the concentration ratio of the Au NPs in the NP‐TiO₂ composite, the performances of OSCs with various polymer active layers are enhanced and efficiency of 8.74% is reached. An integrated optical and electrical model, which takes into account plasmonic‐induced hot carrier tunneling probability and extraction barrier between TiO₂ and the active layer, is introduced. The enhanced charge extraction under plasmonic illumination is attributed to the strong charge injection of plasmonically excited electrons from NPs into TiO₂. The mechanism favors trap filling in TiO₂, which can lower the effective energy barrier and facilitate carrier transport in OSCs.