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The complex gastrointestinal environment and the intestinal epithelial barrier constrain the design and effectiveness of orally administered tumour vaccines. Here we show that outer membrane vesicles (OMVs) fused to a tumour antigen and produced in the intestine by ingested genetically engineered bacteria function as effective tumour vaccines in mice. We modified Escherichia coli to express, under the control of a promoter induced by the monosaccharide arabinose, a specific tumour antigen fused with the protein cytolysin A on the surface of OMVs released by the commensal bacteria. In mice, oral administration of arabinose and the genetically engineered E. coli led to the production of OMVs that crossed the intestinal epithelium into the lamina propria, where they stimulated dendritic cell maturation. In a mouse model of pulmonary metastatic melanoma and in mice bearing subcutaneous colon tumours, the antigen-bearing OMVs inhibited tumour growth and protected the animals against tumour re-challenge. The in situ production of OMVs by genetically modified commensal bacteria for the delivery of stimulatory molecules could be leveraged for the development of other oral vaccines and therapeutics.

Timely clearance of myelin debris is the premise of neuroinflammation termination and tissue regeneration in multiple sclerosis (MS). Microglia are the main scavengers of myelin debris in MS lesions, but its phagocytic capability is limited in MS patients. Here, we develop neutrophil-derived nanovesicles (NNVs) to enhance the efficiency of myelin debris clearance in microglia for MS therapy. RNA sequencing (RNAseq) results demonstrate that NNVs treatment ameliorates lesional neuroinflammation of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Consequently, EAE mice exhibit favorable neurological functions and white matter integrity after NNVs treatment. Specifically, NNVs treatment upregulates the expression of nuclear factor E2-related factor 2 (NRF2) in microglia, as revealed by Assay for Transposase Accessible Chromatin using sequencing (ATACseq). We also demonstrate that NRF2 can activate the transcription of RUBCN (RUN domain and cysteine-rich domain containing Beclin 1-interacting protein), which in turn enhances LC3-associated phagocytosis (LAP) in microglia. As a result, myelin debris engulfed by microglia can be efficiently catabolized in NNVs-treated EAE mice without obvious side effects. Together, this study proves that NNVs can modulate neuroinflammation by clearing myelin debris and is a promising MS treatment strategy.

Overproduction of reactive oxygen species (ROS), a key characteristic of inflammatory bowel disease (IBD), is responsible for dysregulation of signal transduction, inflammatory response, and DNA damage, which ultimately leads to disease progression and deterioration. Thus, ROS scavenging has become a promising strategy to navigate IBD. Inspired by the targeting capability of hyaluronic acid (HA) to CD44-overexpressed inflammatory cells together with the redox regulation capacity of diselenide compounds, we developed an oral nanoformulation

Constructing artificial lymph vessels, which play a key role in the immune response, can provide new insights into immunology and disease pathologies. An immune tissue is a highly complex network that consists of lymph vessels, with a "beads-on-a-string" knotted structure. Herein, we present the facile and rapid fabrication of beads-on-a-string knotted cell-laden fibers using coaxial spinning of alginate by exploiting the Plateau-Rayleigh instability. It is shown how alterations in the flow rate and alginate concentration greatly affect the beads-on-a-string structure, rooted in the Plateau-Rayleigh instability theory. Biocompatibility was confirmed by the lactate dehydrogenase (LDH) assay and live/dead staining of the encapsulated human white blood cells. Finally, the encapsulated white blood cells were still functional as indicated by their anti-CD3 activation to secrete interleukin 2. The rapid fabrication of a cell-laden beads-on-a-string three-dimensional (3D) culture platform enables a crude mimicry of the lymph vessel structure. With joint expertise in immunology, microfluidics, and bioreactors, the technology may contribute to the mechanistic assay of human immune response in vitro and functional replacement.

Compared with traditional chemotherapeutics, vascular disruption agents (VDAs) have the advantages of rapidly blocking the supply of nutrients and starving tumors to death. Although the VDAs are effective under certain scenarios, this treatment triggers angiogenesis in the later stage of therapy that frequently leads to tumor recurrence and treatment failure. Additionally, the nonspecific tumor targeting and considerable side effects also impede the clinical applications of VDAs. Here we develop a customized strategy that combines a VDA with an anti-angiogenic drug (AAD) using mesoporous silica nanoparticles (MSNs) coated with platelet membrane for the self-assembled tumor targeting accumulation. The tailor-made nanoparticles accumulate in tumor tissues through the targeted adhesion of platelet membrane surface to damaged vessel sites, resulting in significant vascular disruption and efficient anti-angiogenesis in animal models. This study demonstrates the promising potential of combining VDA and AAD in a single nanoplatform for tumor eradication.

New strategies to decrease risk of relapse after surgery are needed for improving 5-year survival rate of hepatocellular carcinoma (HCC). To address this need, a wound-targeted nanodrug is developed, that contains an immune checkpoint inhibitor (anti-PD-L1)and an angiogenesis inhibitor (sorafenib)). These nanoparticles consist of highly biocompatible mesoporous silica (MSNP) that is surface-coated with platelet membrane (PM) to achieve surgical site targeting in a self-amplified accumulation manner. Sorafenib is introduced into the MSNP pores while covalently attaching anti-PD-L1 antibody on the PM surface. The resulting nano-formulation, abbreviated as a-PM-S-MSNP, can effectively target the surgical margin when intraperitoneally (IP) administered into an immune competent murine orthotopic HCC model. Multiple administrations of a-PM-S-MSNP generate potent anti-HCC effect and significantly prolong overall mice survival. Immunophenotyping and immunochemistry staining reveal the signatures of favorable anti-HCC immunity and anti-angiogenesis effect at tumor sites. More importantly, microscopic inspection of a-PM-S-MSNP treated mice shows that 2 out 6 are histologically tumor-free, which is in sharp contrast to the control mice where tumor foci can be easily identified. The data suggest that a-PM-S-MSNP can efficiently inhibit post-surgical HCC relapse without obvious side effects and holds considerable promise for clinical translation as a novel nanodrug.

Since the discovery of metal nanoparticles (NPs) in the 1960s, unknown toxicity, cost and the ethical hurdles of research in humans have hindered the translation of these NPs to clinical use. In this work, we demonstrate that Pt NPs with protein coronas are generated in vivo in human blood when a patient is treated with cisplatin. These self-assembled Pt NPs form rapidly, accumulate in tumors, and remain in the body for an extended period of time. Additionally, the Pt NPs are safe for use in humans and can act as anti-cancer agents to inhibit chemotherapy-resistant tumor growth by consuming intracellular glutathione and activating apoptosis. The tumor inhibitory activity is greatly amplified when the Pt NPs are loaded in vitro with the chemotherapeutic drug, daunorubicin, and the formulation is effective even in daunorubicin-resistant models. These in vivo-generated metal NPs represent a biocompatible drug delivery platform for chemotherapy resistant tumor treatment., Platinum based drugs like cisplatin are common chemotherapy treatments for cancer. Here, the authors report on the in situ formation of platinum nanoparticles in patients and demonstrated how platinum nanoparticles can be synthesized using patients’ blood and provide effective drug delivery and cancer treatments.

Microglia are the major innate immune cells in the brain and are essential for maintaining homeostasis in a neuronal microenvironment. Currently, a genetic tool to modify microglial gene expression in specific brain regions is not available. In this report, we introduce a tailor-designed method that uses lipid and polymer hybridized nanoparticles (LPNPs) for the local delivery of small interfering RNAs (siRNAs), allowing the silencing of specific microglial genes in the hypothalamus. Our physical characterization proved that this LPNP-siRNA was uniform and stable. We demonstrated that, due to their natural phagocytic behavior, microglial cells are the dominant cell type taking up these LPNPs in the hypothalamus of rats. We then tested the silencing efficiency of LPNPs carrying a cluster of differentiation molecule 11b (CD11b) or Toll-like receptor 4 (TLR4) siRNA using different in vivo and in vitro approaches. In cultured microglial cells treated with LPNP-CD11b siRNA or LPNP-TLR4 siRNA, we found a silencing efficiency at protein expression levels of 65 or 77%, respectively. In line with this finding, immunohistochemistry and western blotting results from in vivo experiments showed that LPNP-CD11b siRNA significantly inhibited microglial CD11b protein expression in the hypothalamus. Furthermore, following lipopolysaccharide (LPS) stimulation of cultured microglial cells, gene expression of the TLR4 downstream signaling component myeloid differentiation factor 88 and its associated cytokines was significantly inhibited in LPNP-TLR4 siRNA-treated microglial cells compared with cells treated with LPNP-scrambled siRNA. Finally, after LPNP-TLR4 siRNA injection into the rat hypothalamus, we observed a significant reduction in microglial activation in response to LPS compared with the control rats injected with LPNP-scrambled siRNA. Our results indicate that LPNP-siRNA is a promising tool to manipulate microglial activity locally in the brain and may serve as a prophylactic approach to prevent microglial dysfunction-associated diseases.

Iron is an essential element for cell proliferation and homeostasis by engaging in cell metabolism including DNA synthesis, cell cycle, and redox cycling; however, iron overload could contribute to tumor initiation, proliferation, metastasis, and angiogenesis. Therefore, manipulating iron metabolisms, such as using iron chelators, transferrin receptor 1 (TFR1) Abs, and cytotoxic ligands conjugated to transferrin, has become a considerable strategy for cancer therapy. However, there remain major limitations for potential translation to the clinic based on the regulation of iron metabolism in cancer treatment. Nanotechnology has made great advances for cancer treatment by improving the therapeutic potential and lowering the side-effects of the proved drugs and those under various stages of development. Early studies that combined nanotechnology with therapeutic means for the regulation of iron metabolism have shown certain promise for developing specific treatment options based on the intervention of cancer iron acquisition, transportation, and utilization. In this review, we summarize the current understanding of iron metabolism involved in cancer and review the recent advances in iron-regulatory nanotherapeutics for improved cancer therapy. We also envision the future development of nanotherapeutics for improved treatment for certain types of cancers.

The purpose of this work is to explore the effects of novel absorption enhancers on the nasal absorption of nalmefene hydrochloride (NMF). First, the influence of absorption enhancers with different concentrations and types and drug concentrations on the nasal absorption of NMF was investigated in vivo in rats. The absorption enhancers studied include n-dodecyl-β-D-maltoside (DDM), hydroxypropyl-β-cyclodextrin (HP-β-CD), and polyethylene glycol (15)-hydroxy Stearate (Solutol®HS15). At the same time, the in situ toad palate model and rat nasal mucosa model were used to assess the cilia toxicity. The results showed that all the absorption enhancers investigated significantly promote the nasal absorption of NMF, but with different degrees and trends. Among them, the 0.5% (w/v) DDM had the strongest enhancement effect, followed by 0.5% (w/v) Solutol®HS15, 0.25% (w/v) DDM, 0.25% (w/v) Solutol®HS15, 0.1% (w/v) Solutol®HS15, 0.1% (w/v) DDM, and 0.25% (w/v) HP-β-CD, with absolute bioavailability of 76.49%, 72.14%, 71.00%, 69.46%, 60.41%, 59.42%, and 55.18%, respectively. All absorption enhancers exhibited good safety profiles in nasal ciliary toxicity tests. From the perspective of enhancing effect and safety, we considered DDM to be a promising nasal absorption enhancer. And in addition to DDM, Solutol®HS15 can also promote intranasal absorption of NMF, which will provide another option for the development of nalmefene hydrochloride nasal spray.

Dendritic cells (DCs)-based vaccines are an approved method for inducing potent antigen-specific immune responses to eliminate tumor cells. However, this promising strategy still faces challenges such as tumor-associated antigens (TAAs) loading, lymph node homing, quality control, and other limitations. Here, a personalized DC-mimicking nanovaccine (nanoDC) for stimulation of TAAs-specific T cell populations is developed. The nanoDCs are fabricated using nanoparticles with dendritic structure and membranes from mature bone-marrow-derived cells (BMDCs). Mature BMDCs are stimulated by nanostructures assembled from Escherichia coli and tumor cells to efficiently deliver TAAs and induce BMDCs maturation through the stimulator of interferon genes (STING) pathway. By maintaining co-stimulatory markers, molecules class I (MHC-I) antigen complexes and lymphocyte homing receptors, nanoDCs efficiently migrate to lymph nodes and generate potent antigen-specific T cell responses. Consequently, vaccination with nanoDCs strongly inhibits the tumor growth and metastases formation in vivo. In particular, nanoDCs can also induce memory T cells for long-term protective immunity. This study demonstrates that nanoDCs can trigger adaptive immune protection against tumors for personalized immunotherapy and precision medicine.

The most immune cells infiltrating tumor microenvironment (TME), tumor-associated macrophages (TAMs) closely resemble immunosuppressive M2-polarized macrophages. Moreover, tumor cells exhibit high expression of CD47 "don't eat me" signal, which obstructs macrophage phagocytosis. The precise and efficient activation of TAMs is a promising approach to tumor immunotherapy; however, re-education of macrophages remains a challenge. Bacteria-derived outer membrane vesicles (OMVs) are highly immunogenic nanovesicles that can robustly stimulate macrophages. Here, an OMV-based controllable two-way adaptor is reported, in which a CD47 nanobody (CD47nb) is fused onto OMV surface (OMV-CD47nb), with the outer surface coated with a polyethylene glycol (PEG) layer containing diselenide bonds (PEG/Se) to form PEG/Se@OMV-CD47nb. The PEG/Se layer modification not only mitigates the immunogenicity of OMV-CD47nb, thereby remarkedly increasing the dose that can be administered safely through intravenous injection, but also equips the formulation with radiation-triggered controlled release of OMV-CD47nb. Application of radiation to tumors in mice injected with the nanoformulation results in remodeling of TME. As two-way adaptors, OMV-CD47nb activates TAM phagocytosis of tumor cells via multiple pathways, including induction of M1 polarization and blockade of "don't eat me" signal. Moreover, this activation of TAMs results in the stimulation of T cell-mediated antitumor immunity through effective antigen presentation.

Surgery is one of the main effective strategies for the treatment of solid tumors, but high postoperative recurrence is also the main cause of death in current cancer therapy. The prevention of postoperative hepatocellular carcinoma (HCC) recurrence is a clinical problem that needs to be solved urgently. At present, there are still some problems to be solved, such as, how to achieve free drugs to target the site of surgical resection; develop a strategy for the simultaneous administration of multiple drugs to inhibit postoperative recurrence; and provide the appropriate animal model that mimics the process of postoperative HCC recurrence. In this study, we used a facile and reproducible method to successfully prepare amphiphilic Janus nanoparticles (JNPs). In order to improve targeting of the JNPs to residual HCC cells after surgery, we modified the side of gold nanorods (GNRs) with lactobionic acid (LA), thus creating LA-JNPs. This provided an active and targeted co-delivery system for hydrophilic and hydrophobic drugs in separate rooms, thus avoiding mutual effects. Next, we established two models to simulate postoperative HCC recurrence: a subcutaneous postoperative recurrence model based on patient-derived tumor xenograft (PDX) tissues and a postoperative recurrence model of orthotopic HCC. By applying these models, the enhanced permeability and retention effect (EPR) based tumor targeting and LA based active targeting can jointly promote the enrichment and uptake of JNPs at tumor site. LA-JNPs represented an efficient targeting system for the co-delivery of Sorafenib/Doxorubicin with an optimized anti-recurrence effect and significantly improved the survival of mice during treatment for postoperative recurrence.

To better make nanomedicine entering the clinic, developing new rationally designed nanotherapeutics with a deeper understanding of tumor biology is required. The tumor microenvironment is similar to the inflammatory response in a healing wound, the milieu of which promotes tumor cell invasion and metastasis. Successful targeting of the microenvironmental components with effective nanotherapeutics to modulate the tumor microvessels or restore the homeostatic mechanisms in the tumor stroma will offer new hope for cancer treatment. We here highlight the progress in constructing nanotherapeutics to target or modulate the tumor microenvironment. We discuss the factors necessary for nanomedicines to become a new paradigm in cancer therapy, including the selection of drugs and therapeutic targets, controllable synthesis, and tempo-spatial drug release.

In recent years, tumor microenvironment (TME) has been recognized as potential targets for tumor treatment and the tumor vascular system is one of such targets. Fusing truncated tissue factor (tTF) with pH low insertion peptides (pHLIP), tTF-pHLIP, can target tumor vessels owing to its acidic TME and cause tumor vessel occlusion by blood clotting and subsequently effectively inhibit tumor growth. To evaluate its bioeffects, we exposed the tTF-pHLIP to normal mice and mice xenograft with B16F10 tumor and analyzed the metabolic profiling of various tissues and biofluids including plasma and urine from mice treated with and without tTF-pHLIP. A combination of nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry and ultra-high-performance liquid chromatography-mass spectrometry was employed in the study. We found that tTF-pHLIP treatment can effectively reduce tumor size and concurrently ameliorate tumor-induced alterations in the TCA cycle metabolism and lipid metabolism. In addition, we found that toxicity of tTF-pHLIP to normal mice is minor and exposure of the tTF-pHLIP induced oxidative stress to the system. Hence, we concluded that tTF-pHLIP is of low toxicity and effective in reducing tumor size as well as rebalancing tumor-induced metabolic derailment. Accepted version

Tumor complexity makes the development of highly sensitive tumor imaging probes an arduous task. Here, we construct a peptide-based near-infrared probe that is responsive to fibroblast activation protein-α (FAP-α), and specifically forms nanofibers on the surface of cancer-associated fibroblasts (CAFs) in situ. The assembly/aggregation-induced retention (AIR) effect results in enhanced accumulation and retention of the probe around the tumor, resulting in a 5.5-fold signal enhancement in the tumor 48 h after administration compared to that of a control molecule that does not aggregate. The probe provides a prolonged detectable window of 48 h for tumor diagnosis. The selective assembly of the probe results in a signal intensity over four- and fivefold higher in tumor than in the liver and kidney, respectively. With enhanced tumor imaging capability, this probe can visualize small tumors around 2 mm in diameter.

Expressed in macrophages and endothelial cells, the receptor for angiopoietin, tyrosine kinase with immunoglobulin and epidermal growth factor homology-2 (Tie2), is required for the reconstruction of blood vessels in tumor recurrence after chemotherapy. Thus, small therapeutic peptides that target and block Tie2 activity are promising as a therapeutic for the prevention of tumor relapse after chemotherapy. However, such small peptides often have low bioavailability, undergo rapid enzymatic degradation, and exhibit a short circulation half-life, making them ineffective in cancer therapy. Herein, we designed a dual-responsive amphiphilic peptide (mPEG1000-K(DEAP)-AAN-NLLMAAS) to modify the small peptide T4 (NLLMAAS) as a Tie2 inhibitor, endowing it with the ability to endure in circulation and specifically target tumor tissue. The ultimate nanoformulation (P-T4) releases T4 in response to the combination of the acidic tumor microenvironment and the presence of legumain, which is commonly overexpressed in tu...

After centuries of development, using vaccination to stimulate immunity has become an effective method for prevention and treatment of a variety of diseases including infective diseases and cancers. However, the tailor-made efficient delivery system for specific antigens is still urgently needed due to the low immunogenicity and stability of antigens, especially for vaccines to induce CD8

An effective tumor vaccine vector that can rapidly display neoantigens is urgently needed. Outer membrane vesicles (OMVs) can strongly activate the innate immune system and are qualified as immunoadjuvants. Here, we describe a versatile OMV-based vaccine platform to elicit a specific anti-tumor immune response via specifically presenting antigens onto OMV surface. We first display tumor antigens on the OMVs surface by fusing with ClyA protein, and then simplify the antigen display process by employing a Plug-and-Display system comprising the tag/catcher protein pairs. OMVs decorated with different protein catchers can simultaneously display multiple, distinct tumor antigens to elicit a synergistic antitumour immune response. In addition, the bioengineered OMVs loaded with different tumor antigens can abrogate lung melanoma metastasis and inhibit subcutaneous colorectal cancer growth. The ability of the bioengineered OMV-based platform to rapidly and simultaneously display antigens may facilitate the development of these agents for personalized tumour vaccines., Outer membrane vesicles (OMVs), non-replicative particles secreted by Gram-negative bacteria, are known for their immunostimulatory and adjuvant properties. Here, by employing a Plug-and-Display technology, the authors engineer OMVs to display tumor antigens on the surface, a platform that promotes anti-tumor immune responses in preclinical cancer models.

Therapeutic mRNA vaccination is an attractive approach to trigger antitumor immunity. However, the mRNA delivery technology for customized tumor vaccine is still limited. In this work, bacteria-derived outer membrane vesicles (OMVs) are employed as an mRNA delivery platform by genetically engineering with surface decoration of RNA binding protein, L7Ae, and lysosomal escape protein, listeriolysin O (OMV-LL). OMV-LL can rapidly adsorb box C/D sequence-labelled mRNA antigens through L7Ae binding (OMV-LL-mRNA) and deliver them into dendritic cells (DCs), following by the cross-presentation via listeriolysin O-mediated endosomal escape. OMV-LL-mRNA significantly inhibits melanoma progression and elicits 37.5% complete regression in a colon cancer model. OMV-LL-mRNA induces a long-term immune memory and protects the mice from tumor challenge after 60 days. In summary, this platform provides a delivery technology distinct from lipid nanoparticles (LNPs) for personalized mRNA tumor vaccination, and with a "Plug-and-Display" strategy that enables its versatile application in mRNA vaccines.

Beclin 2 plays a critical role in metabolic regulation and obesity, but its functions in innate immune signaling and cancer development remain largely unknown. Here, we identified Beclin 2 as a critical negative regulator of inflammation and lymphoma development. Mice with homozygous ablation of BCL2-interacting protein 2 (Becn2) developed splenomegaly and lymphadenopathy and markedly increased ERK1/2 and NF-κB signaling for proinflammatory cytokine production. Beclin 2 targeted the key signaling kinases MEKK3 and TAK1 for degradation through an ATG9A-dependent, but ATG16L/Beclin 1/LC3–independent, autophagic pathway. Mechanistically, Beclin 2 recruited MEKK3 or TAK1 through ATG9A to form a complex (Beclin 2-ATG9A-MEKK3) on ATG9A(+) vesicles upon ULK1 activation. Beclin 2 further interacted with STX5 and STX6 to promote the fusion of MEKK3- or TAK1-associated ATG9A(+) vesicles to phagophores for subsequent degradation. Importantly, Becn2-deficient mice had a markedly increased incidence of lymphoma development, with persistent STAT3 activation. Myeloid-specific ablation of MEKK3 (Map3k3) completely rescued the phenotypes (splenomegaly, higher amounts of proinflammatory cytokines, and cancer incidence) of Becn2-deficient mice. Hence, our findings have identified an important role of Beclin 2 in the negative regulation of innate immune signaling and tumor development through an ATG9A-dependent, but ATG16L/Beclin 1/LC3–independent, autophagic pathway, thus providing a potential target for the treatment of inflammatory diseases and cancer.

Here we describe two protocols for the construction of responsive and activable nanomedicines that regulate the tumor microenvironment (TME). The TME is composed of all non-cellular and cellular components surrounding a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules, and extracellular matrix and has a crucial role in tumor initiation, growth, and metastasis. Owing to the relatively stable properties of the TME compared to tumor cells, which exhibit frequent genetic mutations and epigenetic changes, therapeutic strategies targeting the TME using multifunctional nanomedicines hold great potential for anti-tumor therapy. By regulating tumor-associated platelets and pancreatic stellate cells (PSCs), the two major players in the TME, we can effectively manipulate the physiological barriers for enhanced drug delivery and significantly improve the tumor penetration and therapeutic efficacy of chemotherapeutics. The preparation and characterization of the multifunctional nanoparticles takes ~10 h for tumor-associated platelet regulation and 16 h for PSC regulation. These nanoformulations can be readily applied to regulate other components in the TME to realize synergistic or additive anti-tumor activity.

Nucleic acid therapy is and will continue to be of great interest in cancer treatment. The development of nanocarriers with high nucleic acid loading capacity, low toxicity, and specific targeting, with excellent pharmacokinetic/pharmacodynamic profiles, will enable us to realize safe and effective nucleic acid therapy. Tremendous efforts have been directed toward the production of optimized theranostic nanocarriers that can simultaneously provide treatment and real-time monitoring to aid researchers and physicians in making adaptation strategies during early drug development and patient's treatment, respectively. In this review, several nanomaterials with inherent optical and magnetic properties, developed for bioimaging and imaging-guided nucleic acid therapies, are introduced and discussed. In each subsection, the unique characteristics of the corresponding theranostic nanomaterials are reviewed and discussed with examples. Finally, we present the remaining challenges that must be addressed and provide our opinions on the future of nanomaterial medicines for bioimaging and imaging-guided nucleic acid therapy.

Engineered nanoparticles could trigger inflammatory responses and potentiate a desired innate immune response for efficient immunotherapy. Here we report size-dependent activation of innate immune signaling pathways by gold (Au) nanoparticles. The ultrasmall-size (10 nm) trigger the NF-κB signaling pathway. Ultrasmall (4.5 nm) Au nanoparticles (Au4.5) activate the NLRP3 inflammasome through directly penetrating into cell cytoplasm to promote robust ROS production and target autophagy protein-LC3 (microtubule-associated protein 1-light chain 3) for proteasomal degradation in an endocytic/phagocytic-independent manner. LC3-dependent autophagy is required for inhibiting NLRP3 inflammasome activation and plays a critical role in the negative control of inflammasome activation. Au4.5 nanoparticles promote the degradation of LC3, thus relieving the LC3-mediated inhibition of the NLRP3 inflammasome. Finally, we show that Au4.5 nanoparticles could function as vaccine adjuvants to markedly enhance ovalbumin (OVA)-specific antibody production in an NLRP3-dependent pattern. Our findings have provided molecular insights into size-dependent innate immune signaling activation by cell-penetrating nanoparticles and identified LC3 as a potential regulatory target for efficient immunotherapy.

Fenton reaction-mediated oncotherapy is an emerging strategy which uses iron ions to catalytically convert endogenous hydrogen peroxide into hydroxyl radicals, the most reactive oxygen species found in biology, for efficient cancer therapy. However, Fenton reaction efficiency in tumor tissue is typically limited due to restrictive conditions. One strategy to overcome this obstacle is to increase the temperature specifically at the tumor site. Herein, a tumor-targeting iron sponge (TTIS) nanocomposite based on graphdiyne oxide, which has a high affinity for iron is described. TTIS can accumulate in tumor tissue by decoration with a tumor-targeting polymer to enable tumor photoacoustic and magnetic resonance imaging. With its excellent photothermal conversion efficiency (37.5%), TTIS is an efficient photothermal therapy (PTT) agent. Moreover, the heat produced in the process of PTT can accelerate the release of iron ions from TTIS and simultaneously enhance the efficiency of the Fenton reaction, thus achieving a combined PTT and Fenton reaction-mediated cancer therapy. This work introduces a graphdiyne oxide-based iron sponge that exerts an enhanced antitumor effect through PTT and Fenton chemistry.

Mutant KRAS is a known driver oncogene in pancreatic cancer. However, this protein remains an "undruggable" therapeutic target. Inhibiting mutated KRAS expression at the mRNA level is a potentially effective strategy. Recently, a novel CRISPR-Cas effector, Cas13a has been reported to specifically knock down mRNA expression under the guidance of a single CRISPR-RNA in mammalian cells. Here we demonstrate that the CRISPR-Cas13a system can be engineered for targeted therapy of mutant KRAS in pancreatic cancer. In initial screening, we show that the bacterial Cas13a protein and crRNA significantly knock down mutant KRAS mRNA expression, identifying a CRISPR-Cas13a system that can induce up to a 94% knockdown efficiency. Introducing a single mismatch into the crRNA-target duplex enabled the CRISPR-Cas13a system to specifically recognize KRAS-G12D mRNA with no detectable effects on wild-type KRAS mRNA. More importantly, CRISPR-Cas13a-mediated KRAS-G12D mRNA knockdown potently induced apoptosis in vitro and elicited marked tumor shrinkage in mice. Our work describes an optimization strategy for the development of a CRISPR-Cas13a system to affect efficient and specific knockdown of the oncogenic mRNA, establishing the CRISPR-Cas13a system as a flexible, targeted therapeutic tool.

Combination therapeutic regimen is becoming a primary direction for current cancer immunotherapy to broad the antitumor response. Functional nanomaterials offer great potential for steady codelivery of various drugs, especially small molecules, therapeutic peptides, and nucleic acids, thereby realizing controllable drug release, increase of drug bioavailability, and reduction of adverse effects. Herein, a therapeutic peptide assembling nanoparticle that can sequentially respond to dual stimuli in the tumor extracellular matrix was designed for tumor-targeted delivery and on-demand release of a short d-peptide antagonist of programmed cell death-ligand 1 (DPPA-1) and an inhibitor of idoleamine 2,3-dioxygenase (NLG919). By concurrent blockade of immune checkpoints and tryptophan metabolism, the nanoformulation increased the level of tumor-infiltrated cytotoxic T cells and in turn effectively inhibited melanoma growth. To achieve this, an amphiphilic peptide, consisting of a functional 3-diethylaminopropyl i...

Excess iron deposition in the brain often causes oxidative stress-related damage and necrosis of dopaminergic neurons in the substantia nigra and has been reported to be one of the major vulnerability factors in Parkinson's disease (PD). Iron chelation therapy using deferoxamine (DFO) may inhibit this nigrostriatal degeneration and prevent the progress of PD. However, DFO shows very short half-life in vivo and hardly penetrates the blood brain barrier (BBB). Hence, it is of great interest to develop DFO formulations for safe and efficient intracerebral drug delivery. Herein, we report a polymeric nanoparticle system modified with brain-targeting peptide rabies virus glycoprotein (RVG) 29 that can intracerebrally deliver DFO. The nanoparticle system penetrates the BBB possibly through specific receptor-mediated endocytosis triggered by the RVG29 peptide. Administration of these nanoparticles significantly decreased iron content and oxidative stress levels in the substantia nigra and striatum of PD mice and effectively reduced their dopaminergic neuron damage and as reversed their neurobehavioral deficits, without causing any overt adverse effects in the brain or other organs. This DFO-based nanoformulation holds great promise for delivery of DFO into the brain and for realizing iron chelation therapy in PD treatment.

Low chemosensitivity considerably restricts the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer treatment. Using immunohistochemical evaluation, we investigated that decreased expression of human equilibrative nucleoside transporter-1 (hENT1, which is the major GEM transporter across cell membranes) and increased expression of ribonucleotide reductase subunit 2 (RRM2, which decreases the cytotoxicity of GEM) was associated with low GEM chemosensitivity. To solve these problems, we employed a nanomedicine-based formulation of cationic liposomes for co-delivery of GEM along with siRNA targeting RRM2. Due to the specific endocytic uptake mechanism of nanocarriers and gene-silencing effect of RRM2 siRNA, this nanomedicine formulation significantly increased GEM chemosensitivity in tumor models of genetically engineered Panc1 cells with low hENT1 or high RRM2 expression. Moreover, in a series of patient-derived cancer cells, we demonstrated that the therapeutic benefits of the nanomedicine formulations were associated with the expression levels of hENT1 and RRM2. In summary, we found that the essential factors of GEM chemosensitivity were the expression levels of hENT1 and RRM2, and synthesized nanoformulations can overcome these problems. This unique design of nanomedicine not only provides a universal platform to enhance chemosensitivity but also contributes to the precision design and personalized treatment in nanomedicine.

Nanoscale robots have potential as intelligent drug delivery systems that respond to molecular triggers. Using DNA origami we constructed an autonomous DNA robot programmed to transport payloads and present them specifically in tumors. Our nanorobot is functionalized on the outside with a DNA aptamer that binds nucleolin, a protein specifically expressed on tumor-associated endothelial cells, and the blood coagulation protease thrombin within its inner cavity. The nucleolin-targeting aptamer serves both as a targeting domain and as a molecular trigger for the mechanical opening of the DNA nanorobot. The thrombin inside is thus exposed and activates coagulation at the tumor site. Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth. The nanorobot proved safe and immunologically inert in mice and Bama miniature pigs. Our data show that DNA nanorobots represent a promising strategy for precise drug delivery in cancer therapy.

As a potent autophagy inducer, Beclin 1 is essential for the initiation of autophagic cell death, and triggering extensive autophagy by targeted delivery of Beclin 1 to tumors has enormous potential to inhibit tumor growth. Yet, the therapeutic application of Beclin 1 is hampered by its inability to internalize into cells and nonselective biodistribution in vivo. To tackle this challenge, we employed a novel Beclin 1 delivery manner by constructing a functional protein (Trx-pHLIP-Beclin 1, TpB) composed of a thioredoxin (Trx) tag, a pH low insertion peptide (pHLIP), and an evolutionarily conserved motif of Beclin 1. This protein could effectively transport Beclin 1 to breast and ovarian cancer cell lines under weakly acidic conditions (pH 6.5), markedly inhibit tumor cell growth and proliferation, and induce obvious autophagy. Furthermore, the in vivo antitumor efficacy of the functional Beclin 1 against an SKOV3 xenograft tumor mouse model was tested via intravenous injection. TpB preferentially accumulated in tumors and exhibited a significantly higher tumor growth inhibition than the nontargeted Beclin 1 control, whereas no overt side effects were observed. Taken together, this study sheds light on the potential application of TpB as a highly efficient yet safe antitumor agent for cancer treatment.

Aerobic glycolysis enables cancer cells to rapidly take up nutrients (e.g., nucleotides, amino acids, and lipids) and incorporate them into the biomass needed to produce a new cell. In contrast to existing chemotherapy/radiotherapy strategies, inhibiting aerobic glycolysis to limit the adenosine 5′-triphosphate (ATP) yield is a highly efficient approach for suppressing tumor cell proliferation. However, most, if not all, current inhibitors of aerobic glycolysis cause significant adverse effects because of their nonspecific delivery and distribution to nondiseased organs, low bioavailability, and a narrow therapeutic window. New strategies to enhance the biosafety and efficacy of these inhibitors are needed for moving them into clinical applications. To address this need, we developed a liposomal nanocarrier functionalized with a well-validated tumor-targeting peptide to specifically deliver the aerobic glycolysis inhibitor 3-bromopyruvate (3-BP) into the tumor tissue. The nanoparticles effectively targeted tumors after systemic administration into tumor-bearing mice and suppressed tumor growth by locally releasing 3-BP to inhibit the ATP production of the tumor cells. No overt side effects were observed in the major organs. This report demonstrates the potential utility of the nanoparticle-enabled delivery of an aerobic glycolysis inhibitor as an anticancer therapeutic agent.

Targeting B7-H3 chimeric antigen receptor (CAR) T cells has antitumor potential for therapy of non-small cell lung cancer (NSCLC) in preclinical studies. However, CAR T cell therapy remains a formidable challenge for the treatment of solid tumors due to the heterogeneous and immunosuppressive tumor microenvironment (TME). Nanozymes exhibit merits modulating the immunosuppression of the tumor milieu. Here, a synergetic strategy by combination of nanozymes and CAR T cells in solid tumors is described. This nanozyme with dual photothermal-nanocatalytic properties is endowed to remodel TME by destroying its compact structure. It is found that the B7-H3 CAR T cells infused in mice engrafted with the NSCLC cells have superior antitumor activity after nanozyme ablation of the tumor. Importantly, it is found that the changes altered immune-hostile cancer environment, resulting in enhanced activation and infiltration of B7-H3 CAR T cells. The first evidence that the process of combination nanozyme therapy effectively improves the therapeutic index of CAR T cells is presented. Thus, this study clearly supports that the TME-immunomodulated nanozyme is a promising tool to improve the therapeutic obstacles of CAR T cells against solid tumors.

KRAS mutation is the most common genetic event in pancreatic cancer. Whereas KRAS itself has proven difficult to inhibit, agents that target key downstream signals of KRAS, such as RAF, are possibly effective for pancreatic cancer treatment. Because selective BRAF inhibitors paradoxically induce downstream signaling activation, a pan-RAF inhibitor, LY3009120 is a better alternate for KRAS-mutant tumor treatment. Here we explored a new combinational strategy using a YAP inhibitor and LY3009120 in pancreatic cancer treatment. We found that reduced YAP expression closely correlates with longer relapse-free and overall survival of patients. Stable knockdown of YAP significantly inhibited pancreatic cancer cell proliferation and tumor growth. In addition, LY3009120 exhibited a dramatically enhanced antitumor effect in combination with YAP knockdown. YAP depletion blocks the activation of a parallel AKT signal pathway after LY3009120 treatment. Finally, combination with a YAP inhibitor, verteporfin, significantly enhanced the antitumor efficacy of LY3009120. Collectively, our results demonstrate that genetic or pharmacological inhibition of YAP can increase sensitivity to LY3009120 in pancreatic cancer through blocking compensatory activation of a parallel AKT signal pathway, thereby validating a combinatorial approach for treating KRAS-mutant pancreatic cancer.

Accumulation and aggregation of β-amyloid (Aβ) peptides result in neuronal death, leading to cognitive dysfunction in Alzheimer's disease. The self-assembled Aβ molecules form various intermediate aggregates including oligomers that are more toxic to neurons than the mature aggregates, including fibrils. Thus, one strategy to alleviate Aβ toxicity is to facilitate the conversion of Aβ intermediates to larger aggregates such as fibrils. In this study, we designed a peptide named A3 that significantly enhanced the formation of amorphous aggregates of Aβ by accelerating the aggregation kinetics. Thioflavin T fluorescence experiments revealed an accelerated aggregation of Aβ monomers, accompanying reduced Aβ cytotoxicity. Transgenic Caenorhabditis elegans over-expressing amyloid precursor protein exhibited paralysis due to the accumulation of Aβ oligomers, and this phenotype was attenuated by feeding the animals with A3 peptide. These findings suggest that the Aβ aggregation-promotion effect can potentially be useful for developing strategies to reduce Aβ toxicity.

Extensive evidence has shown that platelets support tumor metastatic progression by inducing epithelial-mesenchymal transition of cancer cells and by shielding circulating tumor cells from immune-mediated elimination. Therefore, blocking platelet function represents a potential new avenue for therapy focused on eliminating metastasis. Here we show that liposomal nanoparticles bearing the tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) can deliver a platelet inhibitor, ticagrelor, into tumor tissues to specifically inhibit tumor-associated platelets. The drug-loaded nanoparticles (CREKA-Lipo-T) efficiently blocked the platelet-induced acquisition of an invasive phenotype by tumor cells and inhibited platelet-tumor cell interaction in vitro. Intravenously administered CREKA-Lipo-T effectively targeted tumors within 24 h, and inhibited tumor metastasis without overt side effects. Thus, the CREKA-Lipo formulation provides a simple strategy for the efficient delivery of anti-metastatic drugs and shows considerable promise as a platform for novel cancer therapeutics.

Platinum (Pt)-based chemotherapy is a widely used therapeutic regimen against various cancers. However, the insufficient cellular uptake, deactivation by thiol-containing species and nonspecific distribution of cisplatin (CDDP) result in its low chemosensitivity as well as systemic side effects, which can largely constrain the employment of CDDP in clinical treatment. To circumvent these problems, in this study, polymeric nanoparticles were utilized to co-deliver a water-soluble CDDP derivative, poly (γ, L-glutamic acid)-CDDP conjugate, and a naturally occurring compound derived from broccoli, sulforaphane, which can achieve efficient glutathione (GSH) depletion, to enhance the accumulation of CDDP in cancer cells. Results show that compared with combinational treatment of CDDP and SFN, the nanoparticles were more effectively internalized and could significantly reduce GSH content in breast cancer cells, leading to a notable increase in DNA-bound Pt and DNA damage-induced apoptosis. Moreover, in an orthotopic breast cancer model, the nanoparticles achieved a significantly higher tumor accumulation and exhibited a more powerful anti-tumor activity. Finally, this nano-enhanced chemotherapy was further confirmed in a liver cancer model with high-expression of GSH. Taken together, this sulforaphane-based nano-strategy holds great promise to enhance the sensitivity and therapeutic efficacy of Pt-based chemotherapy.

Metastasis remains the major cause of death in cancer patients. Thus, there is a need to sensitively detect tumor metastasis, especially ultrasmall metastasis, for early diagnosis and precise treatment of cancer. Herein, an ultrasensitive T

Prostate cancer is one of the most common malignant tumors in men, and inhibiting metastasis is a key event but still a major challenge in prostate cancer treatment. Cancer-associated fibroblasts (CAFs) play an important role in prostate tumor metastasis by shaping the malignant tumor microenvironment. Herein, we constructed a CAF-targeting siRNA delivery system by loading the fibroblast activation protein-α (FAP-α) antibody onto the cell-penetrating peptide (CPP)-based nanoparticles, which specifically downregulated C-X-C motif chemokine ligand 12 (CXCL12) expression in CAFs. This regulation generated a series of changes through inactivating CAFs so that the malignant prostate tumor microenvironment was reshaped. The tumor cell invasion, migration, and tumor angiogenesis were significantly inhibited, which all contributed to the suppression of the metastasis of an orthotopic prostate tumor. This tumor microenvironment reshaping strategy

The acquisition of stemness in colorectal cancer (CRC) attributed to the recurrence and metastasis in CRC treatment. Therefore, targeting the stemness of CRC forms a basis for the development of novel therapeutic approaches. However, the pain and systemic side effect from long-term of venipuncture injection remain great challenges to neoplastic treatment. Here, we introduce an oral drug delivery system for sustained release of BMI-1 inhibitor (PTC209) that reverse the stemness of CRC to over-come these obstacles. In this system, nanoparticles modified with hyaluronic acid (HA) showed high-affinity to CD44 / CD168 overexpressed-CRC cells, and efficiently targeted to tumor site in a metastatic orthotropic colon cancer mouse model by oral administration. Significantly, the observed tumor growth inhibition is accompanied by decreased expression of stemness markers in the tumor tissues. Furthermore, HA-NPs-PTC209 also significantly prevented metastasis to the gastrointestinal system, while failing to exhibit acute side effects. In summary, we have developed an orally active, easily synthesized nanomedicine that shows promise for the treatment of colon cancer.

A major challenge in cancer vaccine therapy is the efficient delivery of antigens and adjuvants to stimulate a controlled yet robust tumour-specific T-cell response. Here, we describe a structurally well defined DNA nanodevice vaccine generated by precisely assembling two types of molecular adjuvants and an antigen peptide within the inner cavity of a tubular DNA nanostructure that can be activated in the subcellular environment to trigger T-cell activation and cancer cytotoxicity. The integration of low pH-responsive DNA 'locking strands' outside the nanostructures enables the opening of the vaccine in lysosomes in antigen-presenting cells, exposing adjuvants and antigens to activate a strong immune response. The DNA nanodevice vaccine elicited a potent antigen-specific T-cell response, with subsequent tumour regression in mouse cancer models. Nanodevice vaccination generated long-term T-cell responses that potently protected the mice against tumour rechallenge.

The marked augment of drug-resistance to traditional antibiotics underlines the crying need for novel replaceable antibacterials. Research advances have revealed the considerable sterilization potential of two-dimension graphene-based nanomaterials. Subsequently, two-dimensional nanomaterials beyond graphene (2D NBG) as novel antibacterials have also demonstrated their power for disinfection due to their unique physicochemical properties and good biocompatibility. Therefore, the exploration of antibacterial mechanisms of 2D NBG is vital to manipulate antibacterials for future applications. Herein, we summarize the recent research progress of 2D NBG-based antibacterial agents, starting with a detailed introduction of the relevant antibacterial mechanisms, including direct contact destruction, oxidative stress, photo-induced antibacterial, control drug/metallic ions releasing, and the multi-mode synergistic antibacterial. Then, the effect of the physicochemical properties of 2D NBG on their antibacterial activities is also discussed. Additionally, a summary of the different kinds of 2D NBG is given, such as transition-metal dichalcogenides/oxides, metal-based compounds, nitride-based nanomaterials, black phosphorus, transition metal carbides, and nitrides. Finally, we rationally analyze the current challenges and new perspectives for future study of more effective antibacterial agents. This review not only can help researchers grasp the current status of 2D NBG antibacterials, but also may catalyze breakthroughs in this fast-growing field.

Graphdiyne has attracted much interest from researchers for their potential applications in energy storage, catalysis, and biomedical areas. As one of the derivatives of graphdiyne, graphdiyne quantum dots (GDQDs) may possess superior bioactivity due to active acetylene units. However, the biological application of biocompatible GDQDs have not been reported so far. Herein, GDQDs with uniform size and good crystallization were prepared via a classical solvothermal method. The GDQDs exhibit excitation- and pH-dependent fluorescence emission as well as superior photostability, demonstrating their potential for bioimaging. The GDQDs demonstrate efficient cellular uptake and cell imaging without induction of detectable cytotoxic effects in vitro. Systematical safety evaluation further confirmed good biocompatibility of the GDQDs in vivo. Our study preliminarily validates the application of the GDQDs in biomedicine and encourages more thorough studies for better realizing the potential of GDQDs.

Activated platelets have a high affinity for tumor cells, and consequently, they can protect tumor cells from environmental stress and immune attacks. Therefore, preventing platelet-tumor cell interaction can lead to the elimination of circulating tumor cells via natural killer cells and finally metastasis inhibition. It is also shown that CREKA (Cys-Arg-Glu-Lys-Ala), a tumor-homing pentapeptide, targets fibrin-fibronectin complexes that are found on the tumor stroma and the vessel walls. In this study, we linked CREKA to Ticagrelor, a reversible antagonist of the P2Y12 receptor on platelets. In vitro experiments indicated that CREKA-Ticagrelor could not only inhibit the platelet-induced migration of tumor cells with an invasive phenotype but also prevent tumor-platelet interaction. In vivo antitumor and antimetastasis results of this drug showed that CREKA-Ticagrelor could specifically target the tumor tissues within 24 h post intravenous injection and suppress lung metastasis. Meanwhile, by having this antiplatelet drug targeted, its side effects were minimized, and bleeding risk was decreased. Thus, CREKA-Ticagrelor offers an efficient antimetastatic agent.

Rapid cut-off of blood supply in diseases involving thrombosis is a major cause of morbidity and mortality worldwide. However, the current thrombolysis strategies offer limited results due to the therapeutics' short half-lives, low targeting ability, and unexpected bleeding complications. Inspired by the innate roles of platelets in hemostasis and pathological thrombus, platelet membrane-camouflaged polymeric nanoparticles (nanoplatelets) are developed for targeting delivery of the thrombolytic drug, recombinant tissue plasminogen activator (rt-PA), to local thrombus sites. The tailor-designed nanoplatelets efficiently accumulate at the thrombi in pulmonary embolism and mesenteric arterial thrombosis model mice, eliciting a significantly enhanced thrombolysis activity compared to free rt-PA. In addition, the nanoplatelets exhibit improved therapeutic efficacy over free rt-PA in an ischemic stroke model. Analysis of in vivo coagulation indicators suggests the nanoplatelets might possess a low risk of bleeding complications. The hybrid biomimetic nanoplatelets described offer a promising solution to improve the efficacy and reduce the bleeding risk of thrombolytic therapy in a broad spectrum of thrombosis diseases.

Excessive β-adrenergic stimulation induces cardiac fibrosis and inflammation and eventually leads to heart failure. It remains unclear whether the inflammatory factor and infiltration of macrophages are initiated from cardiac cells or the vascular system. We used 13-nm polyethylene glycol (PEG)-coated gold nanoparticles (GNPs) as size probes because they cannot penetrate normal vascular walls, and we found that over-stimulation of β-adrenoceptors mediates cardiac inflammation and fibrosis by increasing vascular permeability. Stimulation with isoproterenol (ISO, a β-adrenoceptor agonist) induced tissue-specific inflammatory infiltration and fibrosis in the hearts of mice. Consistent with these findings, 13-nm PEG-coated GNP as size probes were also observed to have tissue-specific targeting of the fibrotic heart, indicating over-stimulation of β-adrenoceptors, increased vascular permeability in the heart, and initiated cardiac inflammation and fibrosis.

Within tumors, the coagulation-inducing protein tissue factor (TF), a major initiator of blood coagulation, has been shown to play a critical role in the hematogenous metastasis of tumors, due to its effects on tumor hypercoagulability and on the mediation of interactions between platelets and tumor cells. Targeting tumor-associated TF has therefore great therapeutic potential for antimetastasis therapy and preventing thrombotic complication in cancer patients. Herein, we reported a novel peptide-based nanoparticle that targets delivery and release of small interfering RNA (siRNA) into the tumor site to silence the expression of tumor-associated TF. We showed that suppression of TF expression in tumor cells blocks platelet adhesion surrounding tumor cells in vitro. The downregulation of TF expression in intravenously administered tumor cells (i.e., simulated circulating tumor cells [CTCs]) prevented platelet adhesion around CTCs and decreased CTCs survival in the lung. In a breast cancer mouse model, siRNA-containing nanoparticles efficiently attenuated TF expression in the tumor microenvironment and remarkably reduced the amount of lung metastases in both an experimental lung metastasis model and tumor-bearing mice. What's more, this strategy reversed the hypercoagulable state of the tumor bearing mice by decreasing the generation of thrombin-antithrombin complexes (TAT) and activated platelets, both of which are downstream products of TF. Our study describes a promising approach to combat metastasis and prevent cancer-associated thrombosis, which advances TF as a therapeutic target toward clinic applications.

Combining informative imaging methodologies with effective treatments to destroy tumors is of great importance for oncotherapy. Versatile nanotheranostic agents that inherently possess both diagnostic imaging and therapeutic capabilities are highly desirable to meet these requirements. Here, a simple but powerful nanoplatform based on polydopamine-coated gold nanostar (GNS@PDA), which can be easily diversified to achieve various function extensions, is designed to realize functional and anatomical imaging-guided photothermal oncotherapy. This nanoplatform intrinsically enables computed tomography/photoacoustic/two-photon luminescence/infrared thermal tetramodal imaging and can further incorporate fibroblast activation protein (FAP, a protease highly expressed in most of tumors) activatable near-infrared fluorescence imaging and Fe3+-based magnetic resonance imaging for comprehensive diagnosis. Moreover, GNS@PDA exhibits excellent photothermal performance and efficient tumor accumulation. Under the precise...

Photodynamic therapy (PDT) is a promising anticancer treatment and is clinically approved for different types of tumors. However, current PDT suffers several obstacles, including its neutralization by excess glutathione (GSH) in the tumor tissue and its strongly proangiogenic tumor response. In this work, a biomimic, multifunctional nanoparticle-based PDT agent, combining a tumor-targeted photosensitizer with GSH scavenging and antiangiogenesis therapy, is developed. A porphyrinic Zr-metal-organic framework nanoparticle is used simultaneously as the photosensitizer and the delivery vehicle of vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor apatinib. The core nanoparticles are wrapped in MnO2 to consume the intratumoral GSH and then decorated with a tumor cell membrane camouflage. After intravenous administration, the nanoparticles selectively accumulate in tumor through homotypic targeting mediated by the biomimic decoration, and the combination of enhanced PDT and antiangiogenic drug significantly improves their tumor inhibition efficiency. This study provides an integrated solution for mechanism-based enhancement of PDT and demonstrates the encouraging potential for multifunctional nanosystem applicable for tumor therapy.

Due to their ability to elicit a potent immune reaction with low systemic toxicity, cancer vaccines represent a promising strategy for treating tumors. Considerable effort has been directed toward improving the in vivo efficacy of cancer vaccines, with direct lymph node (LN) targeting being the most promising approach. Here, a click-chemistry-based active LN accumulation system (ALAS) is developed by surface modification of lymphatic endothelial cells with an azide group, which provide targets for dibenzocyclooctyne (DBCO)-modified liposomes, to improve the delivery of encapsulated antigen and adjuvant to LNs. When loading with OVA257-264 peptide and poly(I:C), the formulation elicits an enhanced CD8+ T cell response in vivo, resulting in a much more efficient therapeutic effect and prolonged median survival of mice. Compared to treatment with DBCO-conjugated liposomes (DL)-Ag/Ad without the azide targeting, the percent survival of ALAS-vaccine-treated mice improves by 100% over 60 days. Altogether, the findings indicate that the novel ALAS approach is a powerful strategy to deliver vaccine components to LNs for enhanced antitumor immunity.