MDSC-targeting gold nanoparticles enhance PD-1 tumor immunotherapy by inhibiting NLRP3 inflammasomes.

Myeloid-derived suppressor cells (MDSCs) play a crucial role in the immune escape mechanisms that limit the efficacy of immunotherapeutic strategies. In the tumor microenvironment, NLRP3 inflammasome-driven Interleukin-1ß (IL-1ß) production serves to dampen antitumor immune responses, promoting tumor growth, progression, and immunosuppression. In this study, we revealed that gold nanoparticles (Au NPs) with a size of 30 nm disrupted NLRP3 inflammasome, but not other inflammasomes, in bone marrow-derived macrophages through abrogating NLRP3-NEK7 interactions mediated by reactive oxygen species (ROS). Density functional theory (DFT) calculations provided insights into the mechanism underlying the exceptional ROS scavenging capabilities of Au NPs. Additionally, when coupled with H6, a small peptide targeting MDSCs, Au NPs demonstrated the capacity to effectively reduce IL-1ß levels and diminish the MDSCs population in tumor microenvironment, leading to enhanced T cell activation and increased immunotherapeutic efficacy in mouse tumor models that are sensitive and resistant to PD-1 inhibition. Our findings unraveled a novel approach wherein peptide-modified Au NPs relieved the suppressive impact of the tumor microenvironment by inhibiting MDSCs-mediated IL-1ß release, which is the first time reported the employing a nanostrategy at modulating MDSCs to reverse the immunosuppressive microenvironment and may hold promise as a potential therapeutic agent for cancer immunotherapy.

Nanoreceptors promote mutant p53 protein degradation by mimicking selective autophagy receptors.

In some cancers mutant p53 promotes the occurrence, development, metastasis and drug resistance of tumours, with targeted protein degradation seen as an effective therapeutic strategy. However, a lack of specific autophagy receptors limits this. Here, we propose the synthesis of biomimetic nanoreceptors (NRs) that mimic selective autophagy receptors. The NRs have both a component for targeting the desired protein, mutant-p53-binding peptide, and a component for enhancing degradation, cationic lipid. The peptide can bind to mutant p53 while the cationic lipid simultaneously targets autophagosomes and elevates the levels of autophagosome formation, increasing mutant p53 degradation. The NRs are demonstrated in vitro and in a patient-derived xenograft ovarian cancer model in vivo. The work highlights a possible direction for treating diseases by protein degradation.

Glucosylation endows nanoparticles with TLR4 agonist capability to trigger macrophage polarization and augment antitumor immunity.

Carbohydrates have emerged as promising candidates for immunomodulation, however, how to present them to immune cells and achieve potent immunostimulatory efficacy remains challenging. Here, we proposed and established an effective way of designing unique glyconanoparticles that can amplify macrophage-mediated immune responses through structural mimicry and multiple stimulation. We demonstrate that surface modification with glucose can greatly augment the immunostimulatory efficacy of nanoparticles, comparing to mannose and galactose. In vitro studies show that glucosylation improved the pro-inflammatory efficacy of iron oxide nanoparticles (IONPs) by up to 300-fold, with the immunostimulatory activity of glucosylated IONPs even surpassing that of LPS under certain conditions. In vivo investigation show that glucosylated IONPs elicited increased antitumor immunity and achieved favorable therapeutic outcomes in multiple murine tumor models. Mechanistically, we proposed that glucosylation potentiated the immunostimulatory effect of IONPs by amplifying toll-like receptors 4 (TLR4) activation. Specifically, glucosylated IONPs directly interacted with the TLR4-MD2 complex, resulting in M1 macrophage polarization and enhanced antitumor immunity via activation of NF-κB, MAPK, and STAT1 signaling pathways. Our work provides a simple modification strategy to endow nanoparticles with potent TLR4 agonist effects, which may shed new light on the development of artificial immune modulators for cancer immunotherapy.

PEGylated Manganese-Zinc Ferrite Nanocrystals Combined with Intratumoral Implantation of Micromagnets Enabled Synergetic Prostate Cancer Therapy via Ferroptotic and Immunogenic Cell Death.

Therapeutic efficacy for prostate cancer is highly restricted by insufficient drug accumulation and the resistance to apoptosis and immunogenic cell death (ICD). Although enhanced permeability and retention (EPR) effect of magnetic nanomaterials could benefit from external magnetic field, it falls off rapidly with increased distance from magnet surface. Considering the deep location of prostate in pelvis, the improvement of EPR effect by external magnetic field is limited. In addition, apoptosis resistance and cGAS-STING pathway inhibition-related immunotherapy resistance are major obstacles to conventional therapy. Herein, the magnetic PEGylated manganese-zinc ferrite nanocrystals (PMZFNs) are designed. Instead of providing external magnet, micromagnets into tumor tissues are intratumorally implanted to actively attract and retain intravenously-injected PMZFNs. As a result, PMZFNs accumulate in prostate cancer with high efficacy, depending on the established internal magnetic field, which subsequently elicit potent ferroptosis and the activation of cGAS-STING pathway. Ferroptosis not only directly suppresses prostate cancer but also triggers burst release of cancer-associated antigens and consequently initiates ICD against prostate cancer, where activated cGAS-STING pathway further amplifies the efficacy of ICD by generating interferon-ß. Collectively, the intratumorally implanted micromagnets confer a durable EPR effect of PMZFNs, which eventually achieve the synergetic tumoricidal efficacy with negligible systemic toxicity.

2D-CuPd nanozyme overcome tamoxifen resistance in breast cancer by regulating the PI3K/AKT/mTOR pathway.

Tamoxifen is the most commonly used treatment for estrogen-receptor (ER) positive breast cancer patients, but its efficacy is severely hampered by resistance. PI3K/AKT/mTOR pathway inhibition was proven to augment the benefit of endocrine therapy and exhibited potential for reversing tamoxifen-induced resistance. However, the vast majority of PI3K inhibitors currently approved for clinical use are unsatisfactory in terms of safety and efficacy. We developed two-dimensional CuPd (2D-CuPd) nanosheets with oxidase and peroxidase nanozyme activities to offer a novel solution to inhibit the activity of the PI3K/AKT/mTOR pathway. 2D-CuPd exhibit superior dual nanozyme activities converting hydrogen peroxide accumulated in drug-resistant cells into more lethal hydroxyl radicals while compensating for the insufficient superoxide anion produced by tamoxifen. The potential clinical utility was further demonstrated in an orthotopically implanted tamoxifen-resistant PDX breast cancer model. Our results reveal a novel nanozyme ROS-mediated protein mechanism for the regulation of the PI3K subunit, illustrate the cellular pathways through which increased p85ß protein expression contributes to tamoxifen resistance, and reveal p85ß protein as a potential therapeutic target for overcoming tamoxifen resistance. 2D-CuPd is the first reported nanomaterial capable of degrading PI3K subunits, and its high performance combined with further materials engineering may lead to the development of nanozyme-based tumor catalytic therapy.

FAAH served a key membrane-anchoring and stabilizing role for NLRP3 protein independently of the endocannabinoid system.

NLRP3, the sensor protein of the NLRP3 inflammasome, plays central roles in innate immunity. Over-activation of NLRP3 inflammasome contributes to the pathogenesis of a variety of inflammatory diseases, while gain-of-function mutations of NLRP3 cause cryopyrin-associated periodic syndromes (CAPS). NLRP3 inhibitors, particularly those that inhibit inflammasome assembly and activation, are being intensively pursued, but alternative approaches for targeting NLRP3 would be highly desirable. During priming NLRP3 protein is synthesized on demand and becomes attached to the membranes of ER and mitochondria. Here, we show that fatty acid amide hydrolase (FAAH), the key integral membrane enzyme in the endocannabinoid system, unexpectedly served the critical membrane-anchoring and stabilizing role for NLRP3. The specific interaction between NLRP3 and FAAH, mediated by the NACHT and LRR domains of NLRP3 and the amidase signature sequence of FAAH, was essential for preventing CHIP- and NBR1-mediated selective autophagy of NLRP3. Heterozygous knockout of FAAH, resulting in ~50% reduction in both FAAH and NLRP3 expression, was sufficient to substantially inhibit the auto-inflammatory phenotypes of the NLRP3-R258W knock-in mice, while homozygous FAAH loss almost completely abrogates these phenotypes. Interestingly, select FAAH inhibitors, in particular URB597 and PF-04457845, disrupted NLRP3-FAAH interaction and induced autophagic NLRP3 degradation, leading to diminished inflammasome activation in mouse macrophage cells as well as in peripheral blood mononuclear cells isolated from CAPS patients. Our results unraveled a novel NLRP3-stabilizing mechanism and pinpointed NLRP3-FAAH interaction as a potential drug target for CAPS and other NLRP3-driven diseases.

Crizotinib Nanomicelles Synergize with Chemotherapy through Inducing Proteasomal Degradation of Mutp53 Proteins.

TP53 missense mutations that express highly stabilized mutant p53 protein (mutp53) driving tumorigenesis have been witnessed in a considerable percentage of human cancers. The attempt to induce degradation of mutp53 has thus been an attractive strategy to realize precise antitumor therapy, but currently, there has been no FDA-approved medication for mutp53 cancer. Herein, we discovered a small molecule compound crizotinib, an FDA-approved antitumor drug, exhibited outstanding mutp53-degrading capability. Crizotinib induced ubiquitination-mediated proteasomal degradation of wide-spectrum mutp53 but not the wild-type p53 protein. Degradation of mutp53 by crizotinib eliminated mutp53-conferred gain-of-function (GOF), leading to reduced cell proliferation, migration, demise, and cell cycle arrest, as well as enhanced sensitivity to doxorubicin-elicited killing in mutp53 cancer. To alleviate the side effects and improve the therapeutic effect, we adopted poly(ethylene glycol)-polylactide-co-glycolide (PEG-PLGA) nanomicelles to deliver the hydrophobic drugs doxorubicin and crizotinib, demonstrating that crizotinib nanomicelles effectively enhanced doxorubicin-elicited anticancer efficacy in a p53Y220C pancreatic cancer in vitro and in vivo via mutp53 degradation induced by crizotinib, manifesting its promising application in clinical practice. Our work therefore revealed that crizotinib exerted significant synergistic chemotherapy with doxorubicin and suggested a novel combination therapeutic strategy for targeting p53 cancer in further clinical application.

Proteasomal and autophagy-mediated degradation of mutp53 proteins through mitochondria-targeting aggregation-induced-emission materials.

Close to half of human cancers harbor point mutations in the tumor-suppressor p53 gene, giving rise to the cellular accumulation of mutant p53 (mutp53) proteins with novel neomorphic gain-of-function (GOF) properties. The destruction of mutp53 proteins through either autophagic or proteasomal degradation is a viable strategy for the targeted therapy of p53-mutated cancers. Several nanomaterials, including zinc-iron and ZIF-8 nanoparticles (NPs), have been reported to induce the proteasomal degradation of mutp53 proteins. However, how autophagy, the other major cellular degradative pathway, influences NP-induced mutp53 degradation has not been investigated. This article shows that AIE-Mit-TPP, a mitochondria-targeting material with aggregation-induced emission (AIE) characteristics, elicits ubiquitination-dependent proteasomal degradation of a broad range of mutp53 proteins. Meanwhile, AIE-Mit-TPP also induces massive mitochondrial damage and autophagy. The inhibition of autophagy further increases AIE-Mit-TPP-elicited mutp53 degradation, revealing the negative impact of autophagy on AIE-Mit-TPP-induced mutp53 degradation. As expected, the degradation of mutp53 proteins by AIE-Mit-TPP abrogated mutp53-manifested GOF, leading to reductions in cell proliferation and migration and increases in cell cycle arrest and cell death. Consequently, AIE-Mit-TPP inhibited the growth of mutp53 tumors. This paper unravels the interesting interplay between the proteasomal and autophagic degradative pathways and pinpoints the modulation of autophagy as a potential strategy for optimizing NP-induced mutp53 degradation and p53-targeted cancer therapy. STATEMENT OF SIGNIFICANCE: We have designed three different types of AIE materials: non-targeting (AIE-Br), mitochondria-targeting (AIE-Mit-TPP), lysosome-targeting (AIE-Lyso). Our results proved that mitochondria-targeting AIE material induced degradation of mutp53 proteins via the proteasome degradation pathway and abrogated mutp53-conferred GOF phenotypes. Furthermore, we performed in vitro studies on the effect of the tested materials in mutp53-expressing cancer cells and demonstrated our findings via in vivo investigations in a mouse subcutaneous p53R175H TOV112D ovarian cancer model. Our results confirmed the link between the proteasome pathway and autophagy and thus proposed a strategy of combining AIE-Mit-TPP with autophagy inhibitors for the targeted treatment of mutp53-associated tumors. Finally, we found that AIE-Mit-TPP could induce degradation of a wide-spectrum mutp53 proteins, which makes mitochondria-targeting AIE materials an effective therapeutic strategy for p53-mutated cancers.

PSMA-targeted arsenic nanosheets: a platform for prostate cancer therapy via ferroptosis and ATM deficiency-triggered chemosensitization.

Ferroptosis, a newly recognized form of non-apoptotic cell death, has recently been introduced for effective cancer therapy. The reported ferroptosis-inducing nanomaterials mainly consisted of metal-based components. Herein, we designed an inorganic metal-free nanoplatform, PSMA-targeted arsenic nanosheets (PMANs), which simultaneously increased glutathione (GSH) consumption, suppressed solute carrier family 7 member 11 (SLC7A11) and glutathione-dependent peroxidase 4 (GPX4) expression, and promoted the generation of reactive oxygen species (ROS) and lipid peroxides (LPO). In addition, owing to the large surface area, PMANs efficiently transported doxorubicin (DOX) to prostate cancer for synergistic therapy. Surprisingly, we found that PMANs could sensitize prostate cancer cells to DOX through downregulating the expression of ataxia telangiectasia mutated (ATM), which further augmented the GPX4 downregulation-mediated ferroptotic tumoricidal effect. Given that arsenic trioxide has been routinely and successfully used in the clinical treatment of leukemia for a long time, we anticipate that PMANs will offer a promising strategy for prostate cancer therapy.

Photoresponsive PAMAM-Assembled Nanocarrier Loaded with Autophagy Inhibitor for Synergistic Cancer Therapy.

As one of the most promising drug-delivery carriers due to its small size, easy surface modifiability, and hydrophobic interior, cationic poly(amidoamine) (PAMAM) per se, demonstrated by previous reports and the authors' present study, indicate potential anticancer capability, however, which are restricted by autophagy elicitation. Besides, its side-toxicity profile, having also been extensively documented, limits its translation into the clinic. Herein, the authors design a photoresponsive PAMAM-assembled nanoparticle loaded with the autophagy inhibitor (chloroquine, CQ), which exhibits light responsiveness for precisely controlling drug release and superior dark biosafety. Upon light irradiation, the nanoparticle can dissociate into charged small PAMAM for a significant antitumor effect. Meanwhile, the released CQ can inhibit pro-survival autophagy induced by PAMAM to achieve an excellent synergistic anticancer efficacy in vitro and in vivo. The authors' study provided a vision of utilizing PAMAM as self-carried anticancer therapeutics in combination with an autophagy inhibitor and proposing a cancer therapy with high antitumor efficacy and low side effects to normal tissues.

Glutathionylation-dependent proteasomal degradation of wide-spectrum mutant p53 proteins by engineered zeolitic imidazolate framework-8.

Point mutations within the DNA-binding domain of the TP53 gene occur in a significant percentage of human cancer, leading to cellular accumulation of highly stabilized mutant p53 proteins (mutp53) with tumor-promoting properties. Depletion of mutp53, through inducing either autophagic or proteasomal degradation, is an attractive strategy for the therapy of p53-mutated cancer, but the currently-known degradation inducers, almost exclusively small molecules, are inadequate. Here we show that pH-responsive zeolitic imidazolate framework-8 (ZIF-8) offers a novel solution to mutp53 degradation. ZIF-8 facilitated ubiquitination-mediated and glutathionylation-dependent proteasomal degradation of all of the nine mutp53 we tested, including six hot-spot mutp53, but not the wild-type p53 protein. Sustained elevation of intracellular Zn++ level, resulted from decomposition of the internalized ZIF-8 in the acidic endosomes, decreased the intracellular reduced glutathione (GSH): oxidized glutathione (GSSG) ratio and was essential for mutp53 glutathionylation and degradation. ZIF-8 modified with an Z1-RGD peptide, exhibiting enhanced cellular internalization and improved decomposition behavior, preferentially killed mutp53-expressing cancer cells and demonstrated remarkable therapeutic efficacy in a p53 S241F ES-2 ovarian cancer model as well as in a p53 Y220C patient-derived xenograft (PDX) breast cancer model. The ability to induce wide-spectrum mutp53 degradation gives ZIF-8 a clear advantage over other degradation-inducers, and engineered nanomaterials may be promising alternatives to small molecules for the development of mutp53-targeting drugs.

A blood circulation-prolonging peptide anchored biomimetic phage-platelet hybrid nanoparticle system for prolonged blood circulation and optimized anti-bacterial performance.

Phage therapy holds great promise for resolving the ever-worsening crisis of antibiotic resistance, but it also faces many challenges. One of the issues hampering phage therapy is the short blood residence time of bacteriophages. We have previously identified, through in vivo phage display, a blood circulation-prolonging peptide (BCP1) that was capable of significantly prolonging the blood retention time of a doxorubicin-loaded human ferritin nanocage, leading to enhanced therapeutic efficacy against tumors. Herein, we aimed to extend the application of BCP1 to anti-bacterial phage therapy. Methods: A genetically engineered M13 phage, BCP1-BGL, that displayed the BCP-1 peptide and expressed the restriction endonuclease Bgl II, was constructed. Taking advantage of the fact that BCP1 harbors an RGD motif (a three amino-acid sequence Arg-Gly-Asp with the ability to bind to integrins) and exerts its circulation-prolonging activity primarily through interaction with platelets, we further designed and fabricated a biomimetic phage-platelet hybrid nanoparticle (PPHN) via the physical binding of the BCP1-BGL phage to the platelet membrane nanoparticles derived via a repeated freeze-thaw procedure. A series of experiments in vitro and in vivo were conducted to reveal the long circulation and anti-bacterial capacities of BCP1-BGL phages and PPHNs. Results: The resulting PPHNs possessed a hydrodynamic size of 368 nm in deionized water, with each spherical membranous nanoparticle harboring approximately 12 rod-shaped phage particles stably bound to its surface. PPHNs, which were superior to the BCP1-BGL phages that displayed significantly prolonged anti-bacterial action in vivo against Escherichia coli infection, exhibited further extended blood retention time and optimal anti-bacterial performance in both the prophylactic and treatment approaches. Conclusion: Our work demonstrated a novel strategy in engineering biomimetic phage-based nanoparticles with improved blood retention and anti-bacterial performance and may have implications in phage therapy.

Autophagy Impairment through Lysosome Dysfunction by Brucine Induces Immunogenic Cell Death (ICD).

Autophagy is an important tightly controlled cellular process that regulates cellular homeostasis and is involved in deciding cell fate such as cell survival and death. The role of autophagy in many intracellular signaling pathways explains its interaction with other different types of cell death, including apoptosis and immunogenic cell death (ICD). The reports showed the complex and intriguing relationship existing between autophagy and immune system signaling pathways. However, the role of autophagy in ICD remains to be clearly elucidated. In this study, we demonstrated that Brucine, a clinically-used small molecule in traditional Chinese medicine, elicited autophagy inhibition. Brucine also triggered cell stress and induced features of ICD, including calreticulin (CRT) exposure and high-mobility group box 1 (HMGB1) release in MDA-MB-231 and CT26 cancer cells. Brucine impaired autolysosomal degradation and exerted a feedback regulation of ERK1/2-mTOR-p70S6K signaling cascade. Brucine-elicited ICD was confirmed by the rejection of CT26 tumor cells, implanted in the mice after vaccination with Brucine-treated CT26 cells. The impaired autophagy contributed to Brucine-induced ICD, as knock-down of Atg5 significantly reduced Brucine-elicited CRT exposure and HMGB1 release. Our results revealed Brucine as a novel autophagy regulator, ICD inducer and hitherto undocumented role of autophagy in ICD. Thus, these results imply the importance of Brucine in cancer immunotherapy. Therefore, Brucine may be used as an ICD inducer and improve its application in cancer treatment with minimized toxicity.

Graphene oxide improves postoperative cognitive dysfunction by maximally alleviating amyloid beta burden in mice.

Rationale: Graphene oxide (GO) based nanomaterials have shown potential for the diagnosis and treatment of amyloid-ß (Aß)-related diseases, mainly on Alzheimer's disease (AD). However, these nanomaterials have limitations. How GO is beneficial to eliminate Aß burden, and its physiological function in Aß-related diseases, still needs to be investigated. Moreover, postoperative cognitive dysfunction (POCD) is an Aß-related common central nervous system complication, however, nanomedicine treatment is lacking. Methods: To evaluate the effects of GO on Aß levels, HEK293T-APP-GFP and SHSY5Y-APP-GFP cells are established. Intramedullary fixation surgery for tibial fractures under inhalation anesthesia is used to induce dysfunction of fear memory in mice. The fear memory of mice is assessed by fear conditioning test. Results: GO treatment maximally alleviated Aß levels by simultaneously reducing Aß generation and enhancing its degradation through inhibiting ß-cleavage of amyloid precursor protein (APP) and improving endosomal Aß delivery to lysosomes, respectively. In postoperative mice, the hippocampal Aß levels were significantly increased and hippocampal-dependent fear memory was impaired. However, GO administration significantly reduced hippocampal Aß levels and improved the cognitive function of the postoperative mice. Conclusion: GO improves fear memory of postoperative mice by maximally alleviating Aß accumulation, providing new evidence for the application of GO-based nanomedicines in Aß-related diseases.

Rationally designed rapamycin-encapsulated ZIF-8 nanosystem for overcoming chemotherapy resistance.

Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles are widely reported as a pH-sensitive drug delivery carrier with high loading capacity for tumor therapy. However, the mechanism of intracellular corrosion of ZIF-8 and the corresponding biological effects especially for autophagy response have been rarely reported. Herein, the as-synthesized ZIF-8 was demonstrated to induce mTOR independent and pro-death autophagy. Interestingly, the autophagic process participated in the corrosion of ZIF-8. Subsequently, zinc ion release and the generation of reactive oxygen species due to its corrosion in the acidic compartments were directly responsible for tumor cell killing. In addition, ZIF-8 could sensitize tumor cells to chemotherapy by switching cytoprotective to death promoting autophagy induced by doxorubicin. The mTOR signaling pathway activation was demonstrated to restrict tumor chemotherapy efficiency. Hence, a combined platform rapamycin encapsulated zeolitic imidazolate frameworks (Rapa@ZIF-8) was constructed and demonstrated a more significant chemo-sensitized effect relative to ZIF-8 nanoparticles or rapamycin treatment alone. Lastly, the combined administration of Rapa@ZIF-8 and doxorubicin exhibited an outstanding synergistic antitumor effect without any obvious toxicity to the major organs of mice. Collectively, the optimized nanoplatform, Rapa@ZIF-8, provides a proof of concept for intentionally interfering mTOR pathway and utilizing the switch of survival-to death-promoting autophagy for adjunct chemotherapy.

mTORC1-dependent TFEB nucleus translocation and pro-survival autophagy induced by zeolitic imidazolate framework-8.

A great variety of nanoparticles are known to induce autophagy, leading to either pro-death or pro-survival. Zeolitic imidazolate framework-8 (ZIF-8), a type of porous metal-organic framework (MOF) material and a promising drug delivery vector, has reportedly shown excellent efficacy for cancer therapy. However, less attention has been paid to the potential biological effect of ZIF-8 per se, and if so, how the effect impacts cell fate and therapy outcomes. Herein, we showed that ZIF-8 induced autophagy in HeLa cells, characterized by increased autophagosome formation without disruption of autophagic flux, in a dose- and time-dependent fashion. ZIF-8 also caused dephosphorylation of the transcription factor EB (TFEB) at serine-142 and serine-211, leading to the nucleus translocation of TFEB, an event that promoted lysosome biogenesis and is necessary for autophagy induction. We further pinpointed the inhibition of mTORC1 as the critical event upstream of ZIF-8-elicited TFEB dephosphorylation and the subsequent nucleus translocation. Furthermore, autophagy induced by ZIF-8 promoted cell survival, as inhibiting autophagy by either 3-methyladenine (3-MA) or ATG5 knockdown significantly enhanced ZIF-8-elicited HeLa cell death. Most importantly, doxorubicin-encapsulated ZIF-8 (DOX@ZIF-8) also elicited strong pro-survival autophagy, and the co-delivery of an autophagic inhibitor (3-MA) dramatically enhanced the cytotoxicity of DOX@ZIF-8 in HeLa cells. Our results revealed the unique ability of ZIF-8, both in a free and drug-loaded form, to induce pro-survival autophagy in certain cancer cells, a finding with important implications for potential clinical studies that utilize ZIF-8 as a drug carrier.

Autophagy regulation as a promising approach for improving cancer immunotherapy.

Autophagy plays a critical role in intracellular metabolism and maintaining cellular homeostasis. Certain tumor cells present a higher basal autophagy rate and autophagy inhibition can lead to impaired metabolic dysfunction in autophagy-dependent tumor cells. Autophagy status in immune cells dictates their fate and response to antigen; however, autophagy in immune cells may be beneficial or detrimental depending on the developmental stage of the cell and more specifically its degree of differentiation. Autophagy-deficient hosts present variations in many metabolites, proteins and enzymes that may have tumor-promoting or -inhibiting effects. The centrality of autophagy in the metabolism of some cancers and immune cells poses as a critical target whose mechanisms must be further unraveled to optimize patient response and prevent tumor recurrence.

Pro-Death or Pro-Survival: Contrasting Paradigms on Nanomaterial-Induced Autophagy and Exploitations for Cancer Therapy.

Autophagy is a critical lysosome-mediated cellular degradation process for the clearance of damaged organelles, obsolete proteins, and invading pathogens and plays important roles in the pathogenesis and treatment of human diseases including cancer. While not a cell death process per se, autophagy is nevertheless intimately linked to a cell's live/die decision. Basal autophagy, operating constitutively at low levels in essentially every mammalian cell, is vital for maintaining cellular homeostasis and promotes cell survival. On the other hand, elevated level of autophagy is frequently observed in cells responding to a physical, chemical, or biological stress. This "induced" autophagy, a hallmark under a variety of pathological and pathophysiological conditions, may be either pro-death or pro-survival, two contrasting paradigms for cell fate determination. Research in our laboratory and other groups around the world over the last 15 years has revealed nanomaterials as a unique class of autophagy inducers, with the capability of elevating the cellular autophagy to extremely high levels. In this Account we focus on the contrasting cell fate decision impacted by nanomaterial-induced autophagy. First, we give a brief introduction to nanomaterial-induced autophagy and summarize our current understanding on how it affects a cell's live/die decision. Autophagy induced by nanomaterials, in most cases, promotes cell death, but a significant number of nanomaterials are also able to elicit pro-survival autophagy. Although not a common feature, some nanomaterials may induce pro-death autophagy in one cell type while eliciting pro-survival autophagy in a different cell type. The ability to control the level of the induced autophagy, and furthermore its pro-death/pro-survival nature, is critically important for nanomedicine. Second, we discuss several possible mechanistic insights on the pro-death/pro-survival decision for nanomaterial-induced autophagy. "Disrupted" autophagic processes, with a "block" or perhaps "diversion" at the various stages, may be a characteristic hallmark for nanomaterial-induced autophagy, rendering it intrinsically pro-death in nature. On the other hand, autophagy-mediated upregulation and activation of pro-survival factors or signaling pathways, overriding the intrinsic pro-death nature, may be a common mechanism for nanomaterial-induced pro-survival autophagy. In addition, cargo degradation and reactive oxygen species may also play important roles in the pro-death/pro-survival decision impacted by nanomaterial-induced autophagy. Finally, we focus on the situation where nanomaterials induce autophagy in cancer cells and summarize the different strategies in exploiting the pro-death or pro-survival nature of nanomaterial-induced autophagy to enhance the various modalities of cancer therapy, including direct cancer cell killing, chemotherapy and radiotherapy, photothermal therapy, and integrated diagnosis and therapy. While the details vary, the basic principle is simple and straightforward. If the induced autophagy is pro-death, maximize it. Otherwise, inhibit it. Effective exploitation of nanomaterial-induced autophagy has the potential to become a new weapon in our ever-increasing arsenal to fight cancer, particularly difficult-to-treat and drug-resistant cancer.

Lgr5 in cancer biology: functional identification of Lgr5 in cancer progression and potential opportunities for novel therapy.

Cancer remains one of the leading lethal diseases worldwide. Identifying biomarkers of cancers might provide insights into the strategies for the development of novel targeted anti-cancer therapies. Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) has been recently discovered as a candidate marker of cancer stem cell populations. Aberrant increased expression of Lgr5 may represent one of the most common molecular alterations in some human cancers, leading to long-term potentiation of canonical Wnt/ß-catenin signaling. On the other hand, however, Lgr5-mediated suppression in canonical Wnt/ß-catenin signaling has also been reported in certain cancers, such as B cell malignancies. Until now, therapeutic approaches targeting Lgr5-associated signaling axis are not yet clinically available. Increasing evidence have indicated that endogenous Lgr5+ cell population is implicated in tumor initiation, progression, and metastasis. This review is to summarize our current knowledge about the importance of Lgr5 in cancer biology and the underlying molecular mechanisms of Lgr5-mediated tumor-promoting/suppressive activities, as well as potentially useful preventive strategies in treating tumor. Therefore, targeted therapeutic modulation of Lgr5+ cancer cell population by targeting Wnt/ß-catenin signaling through targeted drug delivery system or targeted genome editing might be promising for potential novel anti-cancer treatments. Simultaneously, combination of therapeutics targeting both Lgr5+ and Lgr5- cancer cells may deserve further consideration considering the plasticity of cancer cells. Also, a more specific targeting of cancer cells using double biomarkers may be much safer and more effective for anti-cancer therapy.