Tumor Antigen Loaded Nanovaccine Induced NIR-Activated Inflammation for Enhanced Antigen Presentation During Immunotherapy of Tumors.

Although anticancer vaccines have achieved certain effects in early clinical practice, T cell immunity as the most common responsive pattern of anticancer vaccines is still limited by unsatisfied tumor recognition and inhibition efficiency. As the critical step of T cell immunity, uptake and presentation of specific antigen by antigen-presenting cells (APC) can be activated by inflammation for enhancing the response of T cells to the antigen source. Here, a hybrid nanovaccine named PTh/MnO2 @M activated with a near-infrared ray (NIR) is prepared by coating an autologous tumor cell membrane on the surface of a polythiophene/MnO2 composite core. The photoelectrical material polythiophene can produce local microinflammation under NIR radiation and activate specific T cell antitumor immunity by promoting APC maturation and autologous tumor antigens presentation. Moreover, the synthesized nanovaccine PTh/MnO2 @M is shown to induce a significant antitumor immune response, effectively inhibit the progression of melanoma in mice, and significantly prolong the survival time of mice in vivo. This strategy aims to enhance T-cell immune responses by promoting antigen presentation, leading to effective and specific cancer therapy.

Multifunctionalized Gold Sub-Nanometer Particles for Sensitizing Radiotherapy against Glioblastoma.

Glioblastoma is the most common lethal malignant intracranial tumor with a low 5-year survival rate. Currently, the maximal safe surgical resection, followed by high-dose radiotherapy (RT), is a standard treatment for glioblastoma. However, high-dose radiation to the brain is associated with brain injury and results in a high fatality rate. Here, integrated pharmaceutics (named D-iGSNPs) composed of gold sub-nanometer particles (GSNPs), blood-brain barrier (BBB) penetration peptide iRGD, and cell cycle regulator α-difluoromethylornithine is designed. In both simulated BBB and orthotopic murine GL261 glioblastoma models, D-iGSNPs are proved to have a beneficial effect on the BBB penetration and tumor targeting. Meanwhile, data from cell and animal experiments reveal that D-iGSNPs are able to sensitize RT. More importantly, the synergy of D-iGSNPs with low-dose RT can exhibit an almost equal therapeutic effect with that of high-dose RT. This study demonstrates the therapeutic advantages of D-iGSNPs in boosting RT, and may provide a facile approach to update the current treatment of glioblastoma.

Bacteria-Mediated Tumor Therapy Utilizing Photothermally-Controlled TNF-α Expression via Oral Administration.

Oral drug administration is widely adopted for diverse drugs and is convenient to use due to the capability of reaching different parts of the body via the bloodstream. However, it is generally not feasible for biomacromolecular antitumor drugs such as protein and nucleic acids due to the limited absorption through gastrointestinal tract (GIT) and the poor tumor targeting. Here, we report a noninvasive thermally sensitive programmable therapetic system using bacteria E. coli MG1655 as an vehicle for tumor treatments via oral administration. Thermally sensitive programmable bacteria (TPB) are transformed with plasmids expressing therapeutic protein TNF-α and then decorated with biomineralized gold nanoparticles (AuNPs) to obtain TPB@Au. AuNPs and TNF-α plasmids efficaciously protected by TPB in the gut can be transported into internal microcirculation via transcytosis of microfold cells (M cells). After that, the bacteria-based antitumor vehicles accumulate at tumor sites due to the anaerobic bacterial feature of homing to tumor microenvironments. In vitro and in vivo experiments verify the successful delivery of AuNPs and TNF-α plasmids by TPB. Importantly, under remote activation the expression of TNF-α in tumor sites can be procisely controlled by the heat generated from photothermal AuNPs to exert therapeutic actions. The biological security evaluation demonstrates that this strategy would not disturb the balance of intestinal flora.

PD-1 Blockade for Improving the Antitumor Efficiency of Polymer-Doxorubicin Nanoprodrug.

Chemotherapy is well recognized to induce immune responses during some chemotherapeutic drugs-mediated tumor eradication. Here, a strategy involving blocking programmed cell death protein 1 (PD-1) to enhance the chemotherapeutic effect of a doxorubicin nanoprodrug HA-Psi-DOX is proposed and the synergetic mechanism between them is further studied. The nanoprodrugs are fabricated by conjugating doxorubicin (DOX) to an anionic polymer hyaluronic acid (HA) via a tumor overexpressed matrix metalloproteinase sensitive peptide (CPLGLAGG) for tumor targeting and enzyme-activated drug release. Once accumulated at the tumor site, the nanoprodrug can be activated to release antitumor drug by tumor overexpressed MMP-2. It is found that HA-Psi-DOX nanoparticles can kill tumor cells effectively and initiate an antitumor immune response, leading to the upregulation of interferon-γ. This cytokine promotes the expression of programmed cell death protein-ligand 1 (PD-L1) on tumor cells, which will cause immunosuppression after interacting with PD-1 on the surface of lymphocytes. The results suggest that the therapeutic efficiency of HA-Psi-DOX nanoparticles is significantly improved when combined with checkpoint inhibitors anti-PD-1 antibody (α-PD1) due to the neutralization of immunosuppression by blocking the interaction between PD-L1 and PD-1. This therapeutic system by combining chemotherapy and immunotherapy further increases the link between conventional tumor therapies and immunotherapy.

A Multifunctional Biomimetic Nanoplatform for Relieving Hypoxia to Enhance Chemotherapy and Inhibit the PD-1/PD-L1 Axis.

Hypoxia is reported to participate in tumor progression, promote drug resistance, and immune escape within tumor microenvironment, and thus impair therapeutic effects including the chemotherapy and advanced immunotherapy. Here, a multifunctional biomimetic core-shell nanoplatform is reported for improving synergetic chemotherapy and immunotherapy. Based on the properties including good biodegradability and functionalities, the pH-sensitive zeolitic imidazolate framework 8 embedded with catalase and doxorubicin constructs the core and serves as an oxygen generator and drug reservoir. Murine melanoma cell membrane coating on the core provides tumor targeting ability and elicits an immune response due to abundance of antigens. It is demonstrated that this biomimetic core-shell nanoplatform with oxygen generation can be partial to accumulate in tumor and downregulate the expression of hypoxia-inducible factor 1α, which can further enhance the therapeutic effects of chemotherapy and reduce the expression of programmed death ligand 1 (PD-L1). Combined with immune checkpoints blockade therapy by programmed death 1 (PD-1) antibody, the dual inhibition of the PD-1/PD-L1 axis elicits significant immune response and presents a robust effect in lengthening tumor recurrent time and inhibiting tumor metastasis. Consequently, the multifunctional nanoplatform provides a potential strategy of synergetic chemotherapy and immunotherapy.

Switching Apoptosis to Ferroptosis: Metal-Organic Network for High-Efficiency Anticancer Therapy.

Discovering advanced materials for regulating cell death is of great importance in the development of anticancer therapy. Herein, by harnessing the recently discovered oxidative stress regulation ability of p53 and the Fenton reaction inducing capability of metal-organic network (MON), MON encapsulated with p53 plasmid (MON-p53) was designed to eradicate cancer cells via ferroptosis/apoptosis hybrid pathway. After confirming the detailed mechanism of MON-p53 in evoking ferroptosis, we further discovered that MON-p53 mediated a "bystander effect" to further sensitize cancer cells toward the MON-p53 induced ferroptosis. A 75-day anticancer experiment indicated that MON-p53 treatment not only suppressed the tumor growth but also prolonged the life-span of tumor bearing mice. Owing to its ability to promote intracellular oxidative stress, MON-p53 decreased the blood metastasis, lung metastasis, and liver metastasis. As a consequence, discovering methods to induce cell ferroptosis would provide a new insight in designing anticancer materials.

A Metal-Polyphenol Network Coated Nanotheranostic System for Metastatic Tumor Treatments.

As a characteristic trait of most tumor types, metastasis is the major cause of the death of patients. In this study, a photothermal agent based on gold nanorod is coated with metal (Gd3+ )-organic (polyphenol) network to realize combination therapy for metastatic tumors. This nanotheranostic system significantly enhances antitumor therapeutic effects in vitro and in vivo with the combination of photothermal therapy (PTT) and chemotherapy, also can remarkably prevent the invasion and metastasis due to the presence of polyphenol. After the treatment, an 81% decrease in primary tumor volumes and a 58% decrease in lung metastasis are observed. In addition, the good performance in magnetic resonance imaging, computerized tomography, and photothermal imaging of the nanotheranostic system can realize image-guided therapy. The multifunctional nanotheranostic system will find a great potential in diagnosis and treatment integration in tumor treatments, and broaden the applications of PTT treatment.

Preferential Cancer Cell Self-Recognition and Tumor Self-Targeting by Coating Nanoparticles with Homotypic Cancer Cell Membranes.

The ultimate goal in cancer therapy and diagnosis is to achieve highly specific targeting to cancer cells. Coated with the source cancer cell membrane specifically derived from the homologous tumors, the nanoparticles are identified with the self-recognition internalization by the source cancer cell lines in vitro and the highly tumor-selective targeting "homing" to the homologous tumor in vivo even in the competition of another heterologous tumor. As the result, MNP@DOX@CCCM nanovehicle showed strong potency for tumor treatment in vivo and the MR imaging. This bioinspired strategy shows great potential for precise therapy/diagnosis of various tumors merely by adjusting the cell membrane source accordingly on the nanoparticle surface.

Highly Integrated Nano-Platform for Breaking the Barrier between Chemotherapy and Immunotherapy.

Fighting metastasis is a major challenge in cancer therapy, and stimulation of the immune system is of particular importance in the treatment of metastatic cancers. Here, an integrated theranostic nanoplatform was developed for the efficient treatment of highly metastatic tumors. Versatile functions including "And" logically controlled drug release, prolonged circulation time, tumor targeting, and anti-metastasis were integrated into doxorubicin (DOX) loaded, highly integrated mesoporous silica nanoparticles (DOX@HIMSNs) for a systemic treatment of highly metastatic triple negative breast cancer (TNBC). It was found that the good therapeutic effect of DOX@HIMSN was only partially attributed to its anticancer cytotoxicity. Most importantly, DOX@HIMSN could induce anticancer immune responses including dendritic cell (DC) maturation and antitumor cytokine release. Compared with the traditional tumor chemotherapy, the integrated theranostic nanoplatform we developed not only improved the tumor specific cytotoxicity but also stimulated antitumor immune responses during the treatment.

Programmed Nanococktail for Intracellular Cascade Reaction Regulating Self-Synergistic Tumor Targeting Therapy.

In this work, a ZnO based nanococktail with programmed functions is designed and synthesized for self-synergistic tumor targeting therapy. The nanococktail can actively target tumors via specific interaction of hyaluronic acid (HA) with CD44 receptors and respond to HAase-rich tumor microenvironment to induce intracellular cascade reaction for controlled therapy. The exposed cell-penetrating peptide (R8) potentiates the cellular uptake of therapeutic nanoparticles into targeted tumor cells. Then ZnO cocktail will readily degrade in acidic endo/lysosomes and induce the production of desired reactive oxygen species (ROS) in situ. The destructive ROS not only leads to serious cell damage but also triggers the on-demand drug release for precise chemotherapy, thus achieving enhanced antitumor efficiency synergistically. After tail vein injection of ZnO cocktail, a favorable tumor apoptosis rate (71.2 ± 8.2%) is detected, which is significantly superior to that of free drug, doxorubicin (12.9 ± 5.2%). Both in vitro and in vivo studies demonstrate that the tailor-made ZnO cocktail with favorable biocompatibility, promising tumor specificity, and self-synergistically therapeutic capacity opens new avenues for cancer therapy.

Nanoparticles Hitchhike on Monocytes for Glioblastoma Treatment after Low-Dose Radiotherapy.

Glioblastomas (GBMs) are aggressive primary brain tumors with fatal outcome. Traditional chemo-radiotherapy has poor therapeutic effect and significant side effects, due to the drug and radiotherapy (RT) resistance, natural blood-brain barrier, and high-dose RT damage. Even more, tumor-associated monocytes (macrophages and microglia, TAMs) constitute up to 30%-50% of the GBM cellular content, and the tumor microenvironment (TME) in GBM is extremely immunosuppressive. Here, we synthesized nanoparticles (D@MLL) that hitchhike on circulating monocytes to target intracranial GBMs with the assistance of low-dose RT. The chemical construction of D@MLL was DOX·HCl loaded MMP-2 peptide-liposome, which could target monocytes by the surface modified lipoteichoic acid. First, low-dose RT at the tumor site increases monocyte chemotaxis and induces M1 type polarization of TAMs. Subsequently, the intravenous injected D@MLL targets circulating monocytes and hitchhikes with them to the central site of the GBM area. DOX·HCl was then released by the MMP-2 response, inducing immunogenic cell death, releasing calreticulin and high-mobility group box 1. This further contributed to TAMs M1-type polarization, dendritic cell maturation, and T cell activation. This study demonstrates the therapeutic advantages of D@MLL delivered by endogenous monocytes to GBM sites after low-dose RT, and it provides a high-precision treatment for GBMs.

In Situ Sprayed Biotherapeutic Gel Containing Stable Microbial Communities for Efficient Anti-Infection Treatment.

Systematic administration of antibiotics to treat infections often leads to the rapid evolution and spread of multidrug-resistant bacteria. Here, an in situ-formed biotherapeutic gel that controls multidrug-resistant bacterial infections and accelerates wound healing is reported. This biotherapeutic gel is constructed by incorporating stable microbial communities (kombucha) capable of producing antimicrobial substances and organic acids into thermosensitive Pluronic F127 (polyethylene-polypropylene glycol) solutions. Furthermore, it is found that the stable microbial communities-based biotherapeutic gel possesses a broad antimicrobial spectrum and strong antibacterial effects in diverse pathogenic bacteria-derived xenograft infection models, as well as in patient-derived multidrug-resistant bacterial xenograft infection models. The biotherapeutic gel system considerably outperforms the commercial broad-spectrum antibacterial gel (0.1% polyaminopropyl biguanide) in pathogen removal and infected wound healing. Collectively, this biotherapeutic strategy of exploiting stable symbiotic consortiums to repel pathogens provides a paradigm for developing efficient antibacterial biomaterials and overcomes the failure of antibiotics to treat multidrug-resistant bacterial infections.

Inhalable Capsular Polysaccharide-Camouflaged Gallium-Polyphenol Nanoparticles Enhance Lung Cancer Chemotherapy by Depleting Local Lung Microbiota.

Local lung microbiota is closely associated with lung tumorigenesis and therapeutic response. It is found that lung commensal microbes induce chemoresistance in lung cancer by directly inactivating therapeutic drugs via biotransformation. Accordingly, an inhalable microbial capsular polysaccharide (CP)-camouflaged gallium-polyphenol metal-organic network (MON) is designed to eliminate lung microbiota and thereby abrogate microbe-induced chemoresistance. As a substitute for iron uptake, Ga3+ released from MON acts as a "Trojan horse" to disrupt bacterial iron respiration, effectively inactivating multiple microbes. Moreover, CP cloaks endow MON with reduced immune clearance by masquerading as normal host-tissue molecules, significantly increasing residence time in lung tissue for enhanced antimicrobial efficacy. In multiple lung cancer mice models, microbe-induced drug degradation is remarkably inhibited when drugs are delivered by antimicrobial MON. Tumor growth is sufficiently suppressed and mouse survival is prolonged. The work develops a novel microbiota-depleted nanostrategy to overcome chemoresistance in lung cancer by inhibiting local microbial inactivation of therapeutic drugs.

Deep-penetration functionalized cuttlefish ink nanoparticles for combating wound infections with synergetic photothermal-immunologic therapy.

The challenge of wound infections post-surgery and open trauma caused by multidrug-resistant bacteria poses a constant threat to clinical treatment. As a promising antimicrobial treatment, photothermal therapy can effectively resolve the problem of drug resistance in conventional antibiotic antimicrobial therapy. Here, we report a deep-penetration functionalized cuttlefish ink nanoparticle (CINP) for photothermal and immunological therapy of wound infections. CINP is decorated with zwitterionic polymer (ZP, namely sulfobetaine methacrylate-methacrylate copolymer) to form CINP@ZP nanoparticles. Natural CINP is found to not only exhibit photothermal destruction of methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli), but also trigger macrophages-related innate immunity and enhance their antibacterial functions. The ZP coating on the surface of CINP enables nanoparticles to penetrate into deeply infected wound environment. In addition, CINP@ZP is further integrated into the thermosensitive Pluronic F127 gel (CINP@ZP-F127). After in situ spraying gel, CINP@ZP-F127 is also documented notable antibacterial effects in mice wound models infected with MRSA and E. coli. Collectively, this approach combining of photothermal therapy with immunotherapy can promote delivery efficiency of nanoparticles to the deep foci of infective wounds, and effectively eliminate wound infections.

A Microbial Community Cultured in Gradient Hydrogel for Investigating Gut Microbiome-Drug Interaction and Guiding Therapeutic Decisions.

Despite the recognition that the gut microbiota acts a clinically significant role in cancer chemotherapy, both mechanistic understanding and translational research are still limited. Maximizing drug efficacy requires an in-depth understanding of how the microbiota contributes to therapeutic responses, while microbiota modulation is hindered by the complexity of the human body. To address this issue, a 3D experimental model named engineered microbiota (EM) is reported for bridging microbiota-drug interaction research and therapeutic decision-making. EM can be manipulated in vitro and faithfully recapitulate the human gut microbiota at the genus/species level while allowing co-culture with cells, organoids, and isolated tissues for testing drug responses. Examination of various clinical and experimental drugs by EM reveales that the gut microbiota affects drug efficacy through three pathways: immunological effects, bioaccumulation, and drug metabolism. Guided by discovered mechanisms, custom-tailored strategies are adopted to maximize the therapeutic efficacy of drugs on orthotopic tumor models with patient-derived gut microbiota. These strategies include immune synergy, nanoparticle encapsulation, and host-guest complex formation, respectively. Given the important role of the gut microbiota in influencing drug efficacy, EM will likely become an indispensable tool to guide drug translation and clinical decision-making.

Temulence Therapy to Orthotopic Colorectal Tumor via Oral Administration of Fungi-Based Acetaldehyde Generator.

Taking inspiration from percutaneous ethanol injection (PEI) for tumor ablation, an acetaldehyde generator (SC@ZIF@ADH) is constructed for tumor treatment by modifying a metal-organic framework nanocarrier (ZIF), which is loaded with alcohol dehydrogenase (ADH), onto the surface of Saccharomyces cerevisiae (SC). Oral administration of SC@ZIF@ADH can target tumor via mannose-mediated targeting to tumor associated macrophages (TAMs) and generate ethanol at the hypoxic tumor areas. Ethanol is subsequently catalyzed to toxic acetaldehyde by ADH, inducing tumor cells apoptosis and polarizing TAMs toward the anti-tumor phenotype. In vivo animal results show that this acetaldehyde generator can cause a temulence-like reaction in the tumor, significantly inhibiting tumor progression, and might provide an intelligent and nonsurgical substitute for PEI therapy.

Bioinspired nano-vaccine construction by antigen pre-degradation for boosting cancer personalized immunotherapy.

Cancer vaccines-based cancer immunotherapy has drawn widespread concern. However, insufficient cancer antigens and inefficient antigen presentation lead to low immune response rate, which greatly restrict the practical application of cancer vaccines. Here, inspired by intracellular proteasome-mediated protein degradation pathway, we report an antigen presentation simplification strategy by extracellular degradation of antigen proteins into peptides with proteolytic enzyme for improving the utilization of cancer antigens and arousing restricted cancer immunity. The pre-degraded antigen peptides are first validated to exhibit an increased capacity on antigen-presenting cell (APC) stimulation compared with proteins and still reserve antigen specificity and major histocompatibility complex (MHC) affinity. Furthermore, by coordinating the pre-degraded peptides with calcium phosphate nanoparticles (CaP), a CaP-peptide vaccine (CaP-Pep) is constructed, which is verified to induce an efficient personalized immune response in vivo for multi-model anti-cancer therapy. Notably, this bioinspired strategy based on extracellular enzymatic hydrolysis for vaccine construction is not only applicable for multiple types of cancers, but also shows great potential in expanding immunology fields and translational medicine.

Biomaterial-mediated modulation of oral microbiota synergizes with PD-1 blockade in mice with oral squamous cell carcinoma.

Because a host's immune system is affected by host-microbiota interactions, means of modulating the microbiota could be leveraged to augment the effectiveness of cancer therapies. Here we report that patients with oral squamous cell carcinoma (OSCC) whose tumours contained higher levels of bacteria of the genus Peptostreptococcus had higher probability of long-term survival. We then show that in mice with murine OSCC tumours injected with oral microbiota from patients with OSCCs, antitumour responses were enhanced by the subcutaneous delivery of an adhesive hydrogel incorporating silver nanoparticles (which inhibited the growth of bacteria competing with Peptostreptococcus) alongside the intratumoural delivery of the bacterium P. anaerobius (which upregulated the levels of Peptostreptococcus). We also show that in mice with subcutaneous or orthotopic murine OSCC tumours, combination therapy with the two components (nanoparticle-incorporating hydrogel and exogenous P. anaerobius) synergized with checkpoint inhibition with programmed death-1. Our findings suggest that biomaterials can be designed to modulate human microbiota to augment antitumour immune responses.

Neisseria meningitidis Opca Protein/MnO2 Hybrid Nanoparticles for Overcoming the Blood-Brain Barrier to Treat Glioblastoma.

The major hurdle in glioblastoma therapy is the low efficacy of drugs crossing the blood-brain barrier (BBB). Neisseria meningitidis is known to specifically enrich in the central nervous system through the guidance of an outer membrane invasion protein named Opca. Here, by loading a chemotherapeutic drug methotrexate (MTX) in hollow manganese dioxide (MnO2 ) nanoparticles with surface modification of the Opca protein of Neisseria meningitidis, a bionic nanotherapeutic system (MTX@MnO2 -Opca) is demonstrated to effectively overcome the BBB. The presence of the Opca protein enables the drug to cross the BBB and penetrate into tumor tissues. After accumulating in glioblastoma, the nanotherapeutic system catalyzes the decomposition of excess H2 O2 in the tumor tissue and thereby generates O2 , which alleviates tumor hypoxia and enhances the effect of chemotherapy in the treatment of glioblastoma. This bionic nanotherapeutic system may exhibit great potential in the treatment of glioblastoma.

Non-depleting reformation of immunosuppressive myeloid cells to broaden the application of anti-PD therapy.

Traditional methods of depleting tumor-associated myeloid cells via chemotherapy can easily lead to the re-recruitment of them, eventually resulting in chemo-resistance and presenting obstacles in immunotherapy. Herein, we report a nano-educator (NE) that when loaded with all trans retinoic acid (ATRA) and anti-PD-1 antibodies (aPD-1) instructs myeloid cells to assist T cells towards revitalizing anti-PD-1 therapy. In vivo, ATRA converts myeloid-derived suppressor cells (MDSCs) into dendritic cells (DCs), which are essential for anti-PD-1 therapy, while intervening in the polarization of macrophages. Furthermore, aPD-1-armed T cells reboot anti-tumor immunity after suppression relief, which exposes tumor-specific antigens and in turn promotes the maturation of transformed DCs. The nano-platform provides shelter for vulnerable immunomodulatory agents and durable drug release to stimulate intensive immune modulation. We established three types of tumor-bearing mice models with different myeloid cell contents to show the spatiotemporal complementarity of ATRA and aPD-1. The NE re-educates the tumor's guard to assist T cells in enhanced immunotherapy, broadening the application of aPD-1 in the treatment of anti-PD-1-resistant tumors.