Sequential MR Image‐Guided Local Immune Checkpoint Blockade Cancer Immunotherapy Using Ferumoxytol Capped Ultralarge Pore Mesoporous Silica Carriers after Standard Chemotherapy

Herein, ferumoxytol (Fer) capped antiprogrammed cell death‐ligand 1 (PD‐L1) antibodies (aPD‐L1) loaded ultralarge pore mesoporous silica nanoparticles (Fer‐ICB‐UPMSNPs) are formulated for a sequential magnetic resonance (MR) image guided local immunotherapy after cabazitaxel (Cbz) chemotherapy for the treatment of prostate cancer (PC). The highly porous framework of UPMSNP provides a large capacity for aPD‐L1. Fer capping of the pores extends the period of aPD‐L1 release and provides MR visibility of the aPD‐L1 loaded UPMSNP. As‐chosen Cbz chemotherapy prior to the local immunotherapy induces strong immunogenic cell death, dendritic cell maturation, and upregulation of PD‐L1 of tumor cells. Finally, tumor growth inhibition of sequential MR image‐guided local delivery of Fer‐ICB‐UPMSNPs and a tumor specific adoptive immune reaction are demonstrated in the pretreated Tramp C1 PC mouse model with Cbz chemotherapy. The tumor suppression is superior to those obtained with systemic ICB treatment after Cbz, only Fer‐ICB‐UPMSNP or only Cbz. As a proof‐of concept, MR image‐guided local ICB immunotherapy using Fer‐ICB‐UPMSNPs after chemotherapy suggests a new perspective of translational local immunotherapy for patients who are treated with standard chemotherapies.     

Tumor‐Targeted Drug and CpG Delivery System for Phototherapy and Docetaxel‐Enhanced Immunotherapy with Polarization toward M1‐Type Macrophages on Triple Negative Breast Cancers

Cancer immunotherapy has achieved promising clinical responses in recent years owing to the potential of controlling metastatic disease. However, there is a limited research to prove the superior therapeutic efficacy of immunotherapy on breast cancer compared with melanoma and non‐small‐cell lung cancer because of its limited expression of PD‐L1, low infiltration of cytotoxic T lymphocytes (CTLs), and high level of myeloid‐derived suppressor cells (MDSCs). Herein, a multifunctional nanoplatform (FA‐CuS/DTX@PEI‐PpIX‐CpG nanocomposites, denoted as FA‐CD@PP‐CpG) for synergistic phototherapy (photodynamic therapy (PDT), photothermal therapy (PTT) included) and docetaxel (DTX)‐enhanced immunotherapy is successfully developed. The nanocomposites exhibit excellent PDT efficacy and photothermal conversion capability under 650 and 808 nm irradiation, respectively. More significantly, FA‐CD@PP‐CpG with no obvious side effects can remarkably inhibit the tumor growth in vivo based on a 4T1‐tumor‐bearing mice modal. A low dosage of loaded DTX in FA‐CD@PP‐CpG can promote infiltration of CTLs to improve efficacy of anti‐PD‐L1 antibody (aPD‐L1), suppress MDSCs, and effectively polarize MDSCs toward M1 phenotype to reduce tumor burden, further to enhance the antitumor efficacy. Taken together, FA‐CD@PP‐CpG nanocomposites offer an efficient synergistic therapeutic modality in docetaxel‐enhanced immunotherapy for clinical application of breast cancer.     

Codelivery of Anti‐PD‐1 Antibody and Paclitaxel with Matrix Metalloproteinase and pH Dual‐Sensitive Micelles for Enhanced Tumor Chemoimmunotherapy

Immune checkpoint blockade (ICB) is demonstrating great potential in cancer immunotherapy nowadays. Yet, the low response rate to ICB remains an urgent challenge for tumor immunotherapy. A pH and matrix metalloproteinase dual‐sensitive micellar nanocarrier showing spatio‐temporally controlled release of anti‐PD‐1 antibody (aPD‐1) and paclitaxel (PTX) in solid tumors is prepared to realize synergistic cancer chemoimmunotherapy. Antitumor immunity can be activated by PTX‐induced immunogenic cell death (ICD), while aPD‐1 blocks the PD‐1/PD‐L1 axis to suppress the immune escape due to PTX‐induced PD‐L1 up‐regulation, thus resulting in a synergistic antitumor chemoimmunotherapy. Through decoration with a sheddable polyethylene glycol (PEG) shell, the nanodrug may better accumulate in tumors to boost the synergistic antitumor treatment in a mouse melanoma model. The present study demonstrates a potent antitumor chemoimmunotherapy utilizing tumor microenvironment‐sensitive micelles bearing a sheddable PEG layer to mediate site‐specific sequential release of aPD‐1 and PTX.     

Binary Cooperative Prodrug Nanoparticles Improve Immunotherapy by Synergistically Modulating Immune Tumor Microenvironment

Checkpoint blockade immunotherapy is promising for clinical treatment of various malignant tumors. However, checkpoint blockade immunotherapy suffers from a low response rate due to insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment (ITM). In this study, a tumor‐microenvironment‐activatable binary cooperative prodrug nanoparticle (BCPN) is rationally designed to improve immunotherapy by synergistically modulating the immune tumor microenvironment. BCPN is purely constructed from a tumor acidity and reduction dual‐responsive oxaliplatin (OXA) prodrug for triggering immunogenic cell death (ICD) and eliciting antitumor immunity, and a reduction‐activatable homodimer of NLG919 for inactivating indoleamine 2,3‐dioxygenase 1, which is a key regulator for ITM. Upon tumor‐acidity‐triggered cleavage of the poly(ethylene glycol) shell, PN shows negative to positive charge switch for enhanced tumor accumulation and deep penetration. OXA and NLG919 are then activated in the tumor cells via glutathione‐mediated reduction. It is demonstrate that activated OXA promotes intratumoral accumulation of cytotoxic T lymphocytes by triggering ICD of cancer cells. Meanwhile, NLG919 downregulates IDO‐1‐mediated immunosuppression and suppresses regulatory T cells. Most importantly, PN shows much higher efficiency than free OXA or the combination of free OXA and NLG919 to regress tumor growth and prevent metastasis of mouse models of both breast and colorectal cancer.     

Aptamer‐Engineered Natural Killer Cells for Cell‐Specific Adaptive Immunotherapy

Natural killer (NK) cells are a key component of the innate immune system as they can attack cancer cells without prior sensitization. However, due to lack of cell‐specific receptors, NK cells are not innately able to perform targeted cancer immunotherapy. Aptamers are short single‐stranded oligonucleotides that specifically recognize their targets with high affinity in a similar manner to antibodies. To render NK cells with target‐specificity, synthetic CD30‐specific aptamers are anchored on cell surfaces to produce aptamer‐engineered NK cells (ApEn‐NK) without genetic alteration or cell damage. Under surface‐anchored aptamer guidance, ApEn‐NK specifically bind to CD30‐expressing lymphoma cells but do not react to off‐target cells. The resulting specific cell binding of ApEn‐NK triggers higher apoptosis/death rates of lymphoma cells compared to parental NK cells. Additionally, experiments with primary human NK cells demonstrate the potential of ApEn‐NK to specifically target and kill lymphoma cells, thus presenting a potential new approach for targeted immunotherapy by NK cells.     

A Dual‐Bioresponsive Drug‐Delivery Depot for Combination of Epigenetic Modulation and Immune Checkpoint Blockade

Patients with advanced melanoma that is of low tumor‐associated antigen (TAA) expression often respond poorly to PD‐1/PD‐L1 blockade therapy. Epigenetic modulators, such as hypomethylation agents (HMAs), can enhance the antitumor immune response by inducing TAA expression. Here, a dual bioresponsive gel depot that can respond to the acidic pH and reactive oxygen species (ROS) within the tumor microenvironment (TME) for codelivery of anti‐PD1 antibody (aPD1) and Zebularine (Zeb), an HMA, is engineered. aPD1 is first loaded into pH‐sensitive calcium carbonate nanoparticles (CaCO₃ NPs), which are then encapsulated in the ROS‐responsive hydrogel together with Zeb (Zeb‐aPD1‐NPs‐Gel). It is demonstrated that this combination therapy increases the immunogenicity of cancer cells, and also plays roles in reversing immunosuppressive TME, which contributes to inhibiting the tumor growth and prolonging the survival time of B16F10‐melanoma‐bearing mice.     

Intranasal Nanovaccine Confers Homo‐ and Hetero‐Subtypic Influenza Protection

Cross‐protective and non‐invasively administered vaccines are attractive and highly desired for the control of influenza. Self‐assembling nanotechnology provides an opportunity for the development of vaccines with superior performance. In this study, an intranasal nanovaccine is developed targeting the conserved ectodomain of influenza matrix protein 2(M2e). 3‐sequential repeats of M2e (3M2e) is presented on the self‐assembling recombinant human heavy chain ferritin (rHF) cage to form the 3M2e‐rHF nanoparticle. Intranasal vaccination with 3M2e‐rHF nanoparticles in the absence of an adjuvant induces robust immune responses, including high titers of sera M2e‐specific IgG antibodies, T‐cell immune responses, and mucosal secretory‐IgA antibodies in mice. The 3M2e‐rHF nanoparticles also confer complete protection against a lethal infection of homo‐subtypic H1N1 and hetero‐subtypic H9N2 virus. An analysis of the mechanism of protection underlying the intranasal immunization with the 3M2e‐rHF nanoparticle indicates that M2e‐specific mucosal secretory‐IgA and T‐cell immune responses may play critical roles in the prevention of infection. The results suggest that the 3M2e‐rHF nanoparticle is a promising, needle‐free, intranasally administered, cross‐protective influenza vaccine. The use of self‐assembling nanovaccines could be an ideal strategy for developing vaccines with characteristics such as high immunogenicity, cross‐protection, and convenient administration, as well as being economical and suitable for large‐scale production.     

Vesicular Antibodies: A Bioactive Multifunctional Combination Platform for Targeted Therapeutic Delivery and Cancer Immunotherapy

The ability to selectively kill cancerous cell populations while leaving healthy cells unaffected is a key goal in oncology. The use of nanovesicles (NVs) as chemotherapeutic delivery vehicles has been recently proven successful, yet monotherapy with monomodalities remains a significant limitation for solid tumor treatment. Here, as a proof of principle, a novel cell‐membrane‐derived NVs that can display full‐length monoclonal antibodies (mAbs) is engineered. The high affinity and specificity of mAb for tumor‐specific antigens allow these vesicular antibodies (VAs) to selectively deliver a cytotoxic agent to tumor cells and exert potent inhibition effects. These VAs can also regulate the tumor immune microenvironment. They can mediate antibody‐dependent cellular cytotoxicity to eradicate tumor cells via recruitment and activation of natural killer cells in the tumor. Upon further encapsulation with chemotherapeutic agents, the VAs show unequaled cooperative effects in chemotherapy and immunotherapy in tumor‐bearing mice. As far as it is known, this is the first report of a VA‐based multifunctional combination therapy platform. This might lead to additional applications of vesicular antibodies in cancer theranostics.     

T-Cell-Mimicking Nanoparticles for Cancer Immunotherapy

Cancer immunotherapies, including adoptive T cell transfer and immune checkpoint blockades, have recently shown considerable success in cancer treatment. Nevertheless, transferred T cells often become exhausted because of the immunosuppressive tumor microenvironment. Immune checkpoint blockades, in contrast, can reinvigorate the exhausted T cells; however, the therapeutic efficacy is modest in 70–80% of patients. To address some of the challenges faced by the current cancer treatments, here T-cell-membrane-coated nanoparticles (TCMNPs) are developed for cancer immunotherapy. Similar to cytotoxic T cells, TCMNPs can be targeted at tumors via T-cell-membrane-originated proteins and kill cancer cells by releasing anticancer molecules and inducing Fas-ligand-mediated apoptosis. Unlike cytotoxic T cells, TCMNPs are resistant to immunosuppressive molecules (e.g., transforming growth factor-β1 (TGF-β1)) and programmed death-ligand 1 (PD-L1) of cancer cells by scavenging TGF-β1 and PD-L1. Indeed, TCMNPs exhibit higher therapeutic efficacy than an immune checkpoint blockade in melanoma treatment. Furthermore, the anti-tumoral actions of TCMNPs are also demonstrated in the treatment of lung cancer in an antigen-nonspecific manner. Taken together, TCMNPs have a potential to improve the current cancer immunotherapy.     

Boosting Interleukin‐12 Antitumor Activity and Synergism with Immunotherapy by Targeted Delivery with isoDGR‐Tagged Nanogold

The clinical use of interleukin‐12 (IL12), a cytokine endowed with potent immunotherapeutic anticancer activity, is limited by systemic toxicity. The hypothesis is addressed that gold nanoparticles tagged with a tumor‐homing peptide containing isoDGR, an αvβ3‐integrin binding motif, can be exploited for delivering IL12 to tumors and improving its therapeutic index. To this aim, gold nanospheres are functionalized with the head‐to‐tail cyclized‐peptide CGisoDGRG (Iso1) and murine IL12. The resulting nanodrug (Iso1/Au/IL12) is monodispersed, stable, and bifunctional in terms of αvβ3 and IL12‐receptor recognition. Low‐dose Iso1/Au/IL12, equivalent to 18–75 pg of IL12, induces antitumor effects in murine models of fibrosarcomas and mammary adenocarcinomas, with no evidence of toxicity. Equivalent doses of Au/IL12 (a nanodrug lacking Iso1) fail to delay tumor growth, whereas 15 000 pg of free IL12 is necessary to achieve similar effects. Iso1/Au/IL12 significantly increases tumor infiltration by innate immune cells, such as NK and iNKT cells, monocytes, and neutrophils. NK cell depletion completely inhibits its antitumor effects. Low‐dose Iso1/Au/IL12 can also increase the therapeutic efficacy of adoptive T‐cell therapy in mice with autochthonous prostate cancer. These findings indicate that coupling IL12 to isoDGR‐tagged nanogold is a valid strategy for enhancing its therapeutic index and sustaining adoptive T‐cell therapy.     

Tailor-Made Autophagy Cascade Amplification Polymeric Nanoparticles for Enhanced Tumor Immunotherapy

Chemotherapeutics can induce immunogenic cell death (ICD) by triggering autophagy and mediate antitumor immunotherapy. However, using chemotherapeutics alone can only cause mild cell-protective autophagy and be incapable of inducing sufficient ICD efficacy. The participation of autophagy inducer is competent to enhance autophagy, so the level of ICD is promoted and the effect of antitumor immunotherapy is highly increased. Herein, tailor-made autophagy cascade amplification polymeric nanoparticles STF@AHPPE are constructed to enhance tumor immunotherapy. Arginine (Arg), polyethyleneglycol–polycaprolactone, and epirubicin (EPI) are grafted onto hyaluronic acid (HA) via disulfide bond to form the AHPPE nanoparticles and autophagy inducer STF-62247 (STF) is loaded. When STF@AHPPE nanoparticles target to tumor tissues and efficiently enter into tumor cells with the help of HA and Arg, the high glutathione concentration leads to the cleavage of disulfide bond and the release of EPI and STF. Finally, STF@AHPPE induces violent cytotoxic autophagy and strong ICD efficacy. As compared to AHPPE nanoparticles, STF@AHPPE nanoparticles kill the most tumor cells and show the more obvious ICD efficacy and immune activation ability. This work provides a novel strategy for combining tumor chemo-immunotherapy with autophagy induction.     

Prodrug‐Based Versatile Nanomedicine for Enhancing Cancer Immunotherapy by Increasing Immunogenic Cell Death

Nanoparticle‐based tumor immunotherapy has emerged to show great potential for simultaneously regulating the immunosuppressive tumor microenvironment, reducing the unpleasant side effects, and activating tumor immunity. Herein, an excipient‐free glutathione/pH dual‐responsive prodrug nanoplatform is reported for immunotherapy, simply by sequentially liberating 5‐aminolevulinic acid and immunogenically inducing doxorubicin drug molecules, which can leverage the acidity and reverse tumor microenvironment. The obtained nanoplatform effectively boosts the immune system by promoting dendritic cell maturation and reducing the number of immune suppressive immune cells, which shows the enhanced adjunctive effect of anti‐programmed cell death protein 1 therapy. Overall, the prodrug‐based immunotherapy nanoplatform may offer a reliable strategy for improving synergistic antitumor efficacy.     

Platelet Membrane‐Camouflaged Magnetic Nanoparticles for Ferroptosis‐Enhanced Cancer Immunotherapy

Although cancer immunotherapy has emerged as a tremendously promising cancer therapy method, it remains effective only for several cancers. Photoimmunotherapy (e.g., photodynamic/photothermal therapy) could synergistically enhance the immune response of immunotherapy. However, excessively generated immunogenicity will cause serious inflammatory response syndrome. Herein, biomimetic magnetic nanoparticles, Fe₃O₄‐SAS @ PLT, are reported as a novel approach to sensitize effective ferroptosis and generate mild immunogenicity, enhancing the response rate of non‐inflamed tumors for cancer immunotherapy. Fe₃O₄‐SAS@PLT are built from sulfasalazine (SAS)‐loaded mesoporous magnetic nanoparticles (Fe₃O₄) and platelet (PLT) membrane camouflage and triggered a ferroptotic cell death via inhibiting the glutamate‐cystine antiporter system X_c^? pathway. Fe₃O₄‐SAS @ PLT‐mediated ferroptosis significantly improves the efficacy of programmed cell death 1 immune checkpoint blockade therapy and achieves a continuous tumor elimination in a mouse model of 4T1 metastatic tumors. Proteomics studies reveal that Fe₃O₄‐SAS @ PLT‐mediated ferroptosis could not only induce tumor‐specific immune response but also efficiently repolarize macrophages from immunosuppressive M2 phenotype to antitumor M1 phenotype. Therefore, the concomitant of Fe₃O₄‐SAS @ PLT‐mediated ferroptosis with immunotherapy are expected to provide great potential in the clinical treatment of tumor metastasis.     

Three-in-One Oncolytic Adenovirus System Initiates a Synergetic Photodynamic Immunotherapy in Immune-Suppressive Cholangiocarcinoma

Although photodynamic immunotherapy has been promoted in the clinical practice of cholangiocarcinoma, the insensitivity to photodynamic immunotherapy remains to be a great problem. This can be largely attributed to an immune-suppressive tumor microenvironment (TME) manifested as immature myeloid cells and exhausted cytotoxic T lymphocytes. Here, a three-in-one oncolytic adenovirus system PEG-PEI-Adv-Catalase-KillerRed (p-Adv-CAT-KR) has been constructed to multiply, initiate, and enhance immune responses in photodynamic immunotherapy, using genetically-engineered KillerRed as photosensitizer, catalase as in situ oxygen-supplying mediator, and adenovirus as immunostimulatory bio-reproducible carrier. Meanwhile, PEG-PEI is applied to protect adenovirus from circulating immune attack. The administration of p-Adv-CAT-KR induces increased antigen presenting cells, elevated T cell infiltrations, and reduced tumor burden. Further investigation into underlying mechanism indicates that hypoxia inducible factor 1 subunit alpha (Hif-1α) and its downstream PD-1/PD-L1 pathway contribute to the transformation of immune-suppressive TME in cholangiocarcinoma. Collectively, the combination of KillerRed, catalase, and adenovirus brings about multi-amplified antitumor photo-immunity and has the potential to be an effective immunotherapeutic strategy for cholangiocarcinoma.     

Surface‐Engineering of Red Blood Cells as Artificial Antigen Presenting Cells Promising for Cancer Immunotherapy

The development of artificial antigen presenting cells (aAPCs) to mimic the functions of APCs such as dendritic cells (DCs) to stimulate T cells and induce antitumor immune responses has attracted substantial interests in cancer immunotherapy. In this work, a unique red blood cell (RBC)‐based aAPC system is designed by engineering antigen peptide‐loaded major histocompatibility complex‐I and CD28 activation antibody on RBC surface, which are further tethered with interleukin‐2 (IL2) as a proliferation and differentiation signal. Such RBC‐based aAPC‐IL2 (R‐aAPC‐IL2) can not only provide a flexible cell surface with appropriate biophysical parameters, but also mimic the cytokine paracrine delivery. Similar to the functions of matured DCs, the R‐aAPC‐IL2 cells can facilitate the proliferation of antigen‐specific CD8+ T cells and increase the secretion of inflammatory cytokines. As a proof‐of‐concept, we treated splenocytes from C57 mice with R‐aAPC‐IL2 and discovered those splenocytes induced significant cancer‐cell‐specific lysis, implying that the R‐aAPC‐IL2 were able to re‐educate T cells and induce adoptive immune response. This work thus presents a novel RBC‐based aAPC system which can mimic the functions of antigen presenting DCs to activate T cells, promising for applications in adoptive T cell transfer or even in direct activation of circulating T cells for cancer immunotherapy.     

Enhanced Natural Killer Cell Immunotherapy by Rationally Assembling Fc Fragments of Antibodies onto Tumor Membranes

Recent advances in cancer immunotherapy have exploited the efficient potential of natural killer (NK) cells to kill tumor cells through antibody‐dependent cell‐mediated cytotoxicity (ADCC). However, this therapeutic strategy is seriously limited by tumor antigen heterogeneity since antibodies can only recognize specific antigens. In this work, modified antibodies or their Fc fragments that can target solid tumors without the necessity of specific antigen presentation on tumors are developed. Briefly, Fc fragments or therapeutic monoclonal antibodies are conjugated with the N‐terminus of pH low insertion peptide so that they will selectively assemble onto the membrane of solid tumor cells via the conformational transformation of the peptide by responding to the acidic tumor microenvironment. The inserted Fc fragments or antibodies can efficiently activate NK cells, initiating ADCC and killing multiple types of tumor cells, including antigen‐negative cancer cells. In vivo therapeutic results also exhibit significant efficacy on both primary solid tumors and tumor metastasis. These modified Fc fragments and antibodies present strong potential to overcome the limitation of tumor antigen heterogeneity, broadening the applications of NK cell immunotherapy on solid tumor treatment.     

A Biomimetic Nanogenerator of Reactive Nitrogen Species Based on Battlefield Transfer Strategy for Enhanced Immunotherapy

Currently, cell membrane is always utilized for the construction of biomimetic nanoparticles. By contrast, mimicking the intracellular activity seems more meaningful. Inspired by the specific killing mechanism of deoxy‐hemoglobin (Hb) dependent drug (RRx‐001) in hypoxic red blood cells (RBC), this work aims to develop an inner and outer RBC‐biomimetic antitumor nanoplatform that replicates both membrane surface properties and intracellularly certain therapeutic mechanisms of RRx‐001 in hypoxic RBC. Herein, RRx‐001 and Hb are introduced into RBC membrane camouflaged TiO₂ nanoparticles. Upon arrival at hypoxic tumor microenvironment (TME), the biomimetic nanoplatform (R@HTR) is activated and triggers a series of reactions to generate reactive nitrogen species (RNS). More importantly, the potent antitumor immunity and immunomodulatory function of RNS in TME are demonstrated. Such an idea would transfer the battlefield of RRx‐001 from hypoxic RBC to hypoxic TME, enhancing its combat capability. As a proof of concept, this biomimetic nanoreactor of RNS exhibits efficient tumor regression and metastasis prevention. The battlefield transfer strategy would not only present meaningful insights for immunotherapy, but also realize substantial breakthroughs in biomimetic nanotechnology.     

Immune Checkpoint Blockade Mediated by a Small‐Molecule Nanoinhibitor Targeting the PD‐1/PD‐L1 Pathway Synergizes with Photodynamic Therapy to Elicit Antitumor Immunity and Antimetastatic Effects on Breast Cancer

Targeting programmed cell death protein 1 (PD‐1)/programmed death ligand 1 (PD‐L1) immunologic checkpoint blockade with monoclonal antibodies has achieved recent clinical success in antitumor therapy. However, therapeutic antibodies exhibit several issues such as limited tumor penetration, immunogenicity, and costly production. Here, Bristol‐Myers Squibb nanoparticles (NPs) are prepared using a reprecipitation method. The NPs have advantages including passive targeting, hydrophilic and nontoxic features, and a 100% drug loading rate. BMS‐202 is a small‐molecule inhibitor of the PD‐1/PD‐L1 interaction that is developed by BMS. Transfer of BMS‐202 NPs to 4T1 tumor‐bearing mice results in markedly slower tumor growth to the same degree as treatment with anti‐PD‐L1 monoclonal antibody (α‐PD‐L1). Consistently, the combination of Ce6 NPs with BMS‐202 NPs or α‐PD‐L1 in parallel shows more efficacious antitumor and antimetastatic effects, accompanied by enhanced dendritic cell maturation and infiltration of antigen‐specific T cells into the tumors. Thus, inhibition rates of primary and distant tumors reach >90%. In addition, BMS‐202 NPs are able to attack spreading metastatic lung tumors and offer immune‐memory protection to prevent tumor relapse. These results indicate that BMS‐202 NPs possess effects similar to α‐PD‐L1 in the therapies of 4T1 tumors. Therefore, this work reveals the possibility of replacing the antibody used in immunotherapy for tumors with BMS‐202 NPs.     

Cancer Immunotherapy of TLR4 Agonist–Antigen Constructs Enhanced with Pathogen‐Mimicking Magnetite Nanoparticles and Checkpoint Blockade of PD‐L1

Despite the tremendous potential of Toll‐like receptor 4 (TLR4) agonists in vaccines, their efficacy as monotherapy to treat cancer has been limited. Only some lipopolysaccharides (LPS) isolated from particular bacterial strains or structures like monophosphoryl lipid A (MPLA) derived from lipooligosaccharide (LOS), avoid toxic overactivation of innate immune responses while retaining adequate immunogenicity to act as adjuvants. Here, different LOS structures are incorporated into nanoparticle‐filled phospholipid micelles for efficient vaccine delivery and more potent cancer immunotherapy. The structurally unique LOS of the plant pathogen Xcc is incorporated into phospholipid micelles encapsulating iron oxide nanoparticles, producing stable pathogen‐mimicking nanostructures suitable for targeting antigen presenting cells in the lymph nodes. The antigen is conjugated via a hydrazone bond, enabling rapid, easy‐to‐monitor and high‐yield antigen ligation at low concentrations. The protective effect of these constructs is investigated against a highly aggressive model for tumor immunotherapy. The results show that the nanovaccines lead to a higher‐level antigen‐specific cytotoxic T lymphocyte (CTL) effector and memory responses, which when combined with abrogation of the immunosuppressive programmed death‐ligand 1 (PD‐L1), provide 100% long‐term protection against repeated tumor challenge. This nanovaccine platform in combination with checkpoint inhibition of PD‐L1 represents a promising approach to improve the cancer immunotherapy of TLR4 agonists.     

Engineering Stimuli-Activatable Boolean Logic Prodrug Nanoparticles for Combination Cancer Immunotherapy

Prodrug nanoparticles that codeliver the immune modulators to the tumor site are highly recommendable for cancer immunotherapy yet remain challenging. However, effective stimuli-responsive strategies that exploit the endogenous hallmarks of the tumor have paved the way for cancer immunotherapy. For the first time, the development of the Boolean logic prodrug nanoparticles (BLPNs) for tumor-targeted codelivery of immune modulators (e.g., immune activator and immune inhibitor) and combination immunotherapy is reported herein. A library of stimuli-activatable BLPNs is fabricated yielding YES/AND logic outputs by adjusting the input combinations, including extracellular matrix metalloproteins 2/9 (MMP-2/9), intracellular acidity (pH = 5.0–6.0), and reduction (glutathione) in the tumor microenvironment. Tunable and selective control over BLPNs dissociation and prodrug activation is achieved by specifying the connectivity of orthogonal stimuli-labile spacers while exploiting the endogenous signals at the tumor sites. The tumor-specific distribution of the BLPNs and stimuli-activation of the immune modulators for highly efficient cancer immunotherapy are further demonstrated. The results reported in this study may open a new avenue for tumor-specific delivery of immune therapeutics and precise cancer immunotherapy.