Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies due to its immunosuppressive tumor microenvironment. It is hypothesized that overcoming these barriers requires a dual approach: inducing immunogenic tumor cell death (ICD) and enhancing the cancer immunity cycle by exogenous neoantigen targeting on the spleen. In this study, a novel strategy is presented combining irinotecan-loaded silicasomes with spleen-targeting lipid nanoparticles (LNPs) carrying KRASG12D mRNA and the toll-like receptor 7/8 (TLR7/8) agonist 3M-052. The goal is to establish a cancer immunity cycle by promoting endogenous tumor antigen release by the generation of KRAS-specific cytotoxic T cells. Using an orthotopic PDAC mouse model, it is demonstrated that this dual-platform approach significantly reduces tumor burden and extends survival compared to monotherapies. Bulk RNA sequencing and gene expression analyses further reveal synergy between the immune responses at the primary tumor site and the spleen, including maximal upregulation of apoptosis-related genes, endoplasmic reticulum stress pathways, antigen presentation pathways, and T cell activation markers. These findings indicate that the combinatorial strategy effectively bridges innate and adaptive immunity. In conclusion, this study highlights the potential of nanocarrier-based immunotherapy to enhance PDAC immunity by integrating ICD induction with systemic immune reprogramming, offering a promising avenue for improving treatment outcomes.

We demonstrate reprogramming of the tolerogenic immune environment in the liver for mounting an effective immune response against often-fatal pancreatic cancer metastases. This was achieved by engineering a lipid nanoparticle (LNP) to deliver mRNA encoding the KRAS G12D neoantigenic epitope along with cGAMP, a dinucleotide agonist of the stimulator of the interferon genes (STING) pathway, capable of activating a type I interferon response. cGAMP/mKRAS/LNP were synthesized by a microfluidics approach involving nanoprecipitation of mRNA and cGAMP by an ionizable lipid, MC3. Controls included nanoparticles delivering individual components or a wild-type RAS sequence. The dual delivery carrier successfully activated the type I interferon pathway in vitro as well as in vivo, with reprogramming of costimulatory receptor (CD80 and CD86) and MHC-I expression on liver antigen-presenting cells (APC). This allowed the generation of IFN-γ producing cytotoxic T cells, capable of mounting an effective immune response in the metastatic KRAS pancreatic cancer (KPC) mouse model. Noteworthy, intravenous injection of cGAMP/mKRAS/LNP suppressed metastatic growth significantly and prolonged animal survival, both prophylactically and during treatment of established metastases. The protective immune response was mediated by the generation of perforin-releasing CD8+ cytotoxic T cells, engaged in pancreatic cancer cell killing. Importantly, the immune response could also be adoptively transferred by injecting splenocytes (containing memory T cells) from treated into nontreated recipient mice. This study demonstrates that reprogramming the immune-protective niche for metastatic pancreatic cancer can be achieved by the delivery of a STING agonist and mutant KRAS mRNA via ionizable LNPs, offering both prophylactic and therapeutic advantages.

The prevailing desmoplastic stroma and immunosuppressive microenvironment within pancreatic ductal adenocarcinoma (PDAC) pose substantial challenges to therapeutic intervention. Despite the potential of protein tyrosine kinase (PTK) inhibitors in mitigating the desmoplastic stromal response and enhancing the immune milieu, their efficacy is curtailed by suboptimal pharmacokinetics (PK) and insufficient tumor penetration. To surmount these hurdles, we have pioneered a novel strategy, employing lipid bilayer-coated mesoporous silica nanoparticles (termed "silicasomes") as a carrier for the delivery of Nintedanib. Nintedanib, a triple PTK inhibitor that targets vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor receptors, was encapsulated in the pores of silicasomes via a remote loading mechanism for weak bases. This innovative approach not only enhanced pharmacokinetics and intratumor drug concentrations but also orchestrated a transformative shift in the desmoplastic and immune landscape in a robust orthotopic KRAS-mediated pancreatic carcinoma (KPC) model. Our results demonstrate attenuation of vascular density and collagen content through encapsulated Nintedanib treatment, concomitant with significant augmentation of the CD8+/FoxP3+ T-cell ratio. This remodeling was notably correlated with tumor regression in the KPC model. Strikingly, the synergy between encapsulated Nintedanib and anti-PD-1 immunotherapy further potentiated the antitumor effect. Both free and encapsulated Nintedanib induced a transcriptional upregulation of PD-L1 via the extracellular signal-regulated kinase (ERK) pathway. In summary, our pioneering approach involving the silicasome carrier not only improved antitumor angiogenesis but also profoundly reshaped the desmoplastic stromal and immune landscape within PDAC. These insights hold excellent promise for the development of innovative combinatorial strategies in PDAC therapy.

Precision Nutrition by incorporating the effects of genetics, epigenetics, the microbiome, metabolomics, nutrition, exercise, and lifestyle on immune function promises to have many applications in the clinical setting. These potential applications include the role of nutrition in preventing and delaying the development of chronic system-wide inflammation, which has an important impact on the onset of age-related diseases due to its impact on immune function. Research in Precision Nutrition may ultimately lead to a better understanding of the role of diet and nutrients in immune function and will facilitate the development of tailored individualized dietary recommendations to improve human health via improvements in the functioning of the immune system.

Despite the formidable treatment challenges of pancreatic ductal adenocarcinoma (PDAC), considerable progress has been made in improving drug delivery via pioneering nanocarriers. These innovations are geared towards overcoming the obstacles presented by dysplastic stroma and fostering anti-PDAC immune reactions. We are currently conducting research aimed at enhancing chemotherapy to stimulate anti-tumor immunity by inducing immunogenic cell death (ICD). This is accomplished using lipid bilayer-coated nanocarriers, which enable the attainment of synergistic results. Noteworthy examples include liposomes and lipid-coated mesoporous silica nanoparticles known as "silicasomes". These nanocarriers facilitate remote chemotherapy loading, as well as the seamless integration of immunomodulators into the lipid bilayer. In this communication, we elucidate innovative ways for further improving chemo-immunotherapy. The first is the development of a liposome platform engineered by the remote loading of irinotecan while incorporating a pro-resolving lipoxin in the lipid bilayer. This carrier interfered in stromal collagen deposition, as well as boosting the irinotecan-induced ICD response. The second approach was to synthesize polymer nanoparticles for the delivery of mutated KRAS peptides in conjunction with a TLR7/8 agonist. The dual delivery vaccine particle boosted the generation of antigen-specific cytotoxic T-cells that are recruited to lymphoid structures at the cancer site, with a view to strengthening the endogenous vaccination response achieved by chemo-immunotherapy.

Despite efforts to ban asbestos mining and manufacturing, mesothelioma deaths in the United States have remained stable at approximately 2500 cases annually. This trend is not unique to the United States but is also a global phenomenon, associated with increased aging of populations worldwide. Although geoeconomic factors such as lack of regulations and continued asbestos manufacturing in resource-poor countries play a role, it is essential to consider biological factors such as immune senescence and increased genetic instability associated with aging. Recognizing that mesothelioma shares genetic instability and immune system effects with other age-related cancers is crucial because the impact of aging on mesothelioma is frequently assessed in the context of disease latency after asbestos exposure. Nevertheless, the long latency period, often cited as a reason for mesothelioma’s elderly predominance, should not overshadow the shared mechanisms. This communication focuses on the role of immune surveillance in mesothelioma, particularly exploring the impact of immune escape resulting from altered TSG function during aging, contributing to the phylogenetic development of gene mutations and mesothelioma oncogenesis. The interplay between the immune system, TSGs, and aging not only shapes the immune landscape in mesothelioma but also contributes to the development of heterogeneous tumor microenvironments, significantly influencing responses to immunotherapy approaches and survival rates. By understanding the complex interplay between aging, TSG decline, and immune senescence, health care professionals can pave the way for more effective and personalized immunotherapies, ultimately offering hope for better outcomes in the fight against mesothelioma.

Although toll-like receptor (TLR) agonists hold great promise as immune modulators for reprogramming the suppressive immune landscape in pancreatic ductal adenocarcinoma (PDAC), their use is limited by poor pharmacokinetics (PK) and off-target systemic inflammatory effects. To overcome these challenges as well as to attain drug synergy, we developed a lipid bilayer (LB)-coated mesoporous silica nanoparticle (silicasome) platform for co-delivery of the TLR7/8 agonist 3M-052 with the immunogenic chemotherapeutic agent irinotecan. This was accomplished by incorporating the C18 lipid tail of 3M-052 in the coated LB, also useful for irinotecan remote loading in the porous interior. Not only did the co-formulated carrier improve PK, but it strengthened the irinotecan-induced immunogenic cell death response by 3M-052-mediated dendritic cell activation at the tumor site as well as participating lymph nodes. The accompanying increase in CD8+ T-cell infiltration along with a reduced number of regulatory T-cells was associated with tumor shrinkage and metastasis disappearance in subcutaneous and orthotopic KRAS-mediated pancreatic carcinoma tumor models. Moreover, this therapeutic outcome was accomplished without drug or nanocarrier toxicity. All considered, dual-delivery strategies that combine chemo-immunotherapy with co-formulated TLR agonists or other lipid-soluble immune modulators predict successful intervention in heterogeneous PDAC immune landscapes.

While oral desensitization is capable of alleviating peanut allergen anaphylaxis, long-term immune tolerance is the sought-after goal. We developed a liver-targeting lipid nanoparticle (LNP) platform to deliver mRNA-encoded peanut allergen epitopes to liver sinusoidal endothelial cells (LSECs), which function as robust tolerogenic antigen-presenting cells that induce FoxP3+ regulatory T-cells (Tregs). The mRNA strand was constructed by including nucleotide sequences encoding for nonallergenic MHC-II binding T-cell epitopes, identified in the dominant peanut allergen, Ara h2. These epitopes were inserted in the mRNA strand downstream of an MHC-II targeting sequence, further endowed in vitro with 5′ and 3′ capping sequences, a PolyA tail, and uridine substitution. Codon-optimized mRNA was used for microfluidics synthesis of LNPs with an ionizable cationic lipid, also decorated with a lipid-anchored mannose ligand for LSEC targeting. Biodistribution to the liver was confirmed by in vivo imaging, while ELISpot assays demonstrated an increase in IL-10-producing Tregs in the spleen. Prophylactic administration of tandem-repeat or a combination of encapsulated Ara h2 epitopes induced robust tolerogenic effects in C3H/HeJ mice, sensitized to and subsequently challenged with crude peanut allergen extract. In addition to alleviating physical manifestations of anaphylaxis, there was suppression of Th2-mediated cytokine production, IgE synthesis, and mast cell release, accompanied by increased IL-10 and TGF-β production in the peritoneum. Similar efficacy was demonstrated during LNP administration postsensitization. While nondecorated particles had lesser but significant effects, PolyA/LNP-Man lacked protective effects. These results demonstrate an exciting application of mRNA/LNP for treatment of food allergen anaphylaxis, with the promise to be widely applicable to the allergy field.

The purpose of this review is to elucidate how dimensional and durability characteristics of high aspect ratio nanomaterials (HARN), including carbon nanotubes (CNT) and metal nanowires (MeNW), contribute to understanding the fiber pathogenicity paradigm (FPP), including by explaining the structure-activity relationships (SAR) of a diverse range of natural and synthetic elongate materials that may or may not contribute to mesothelioma development in the lung. While the FPP was originally developed to explain the critical importance of asbestos and synthetic vitreous fiber length, width, aspect ratio and biopersistence in mesothelioma development, there are a vast number of additional inhalable materials that need to be considered in terms of pathogenic features that may contribute to mesothelioma or lack thereof. Not only does the ability to exert more exact control over the length and biopersistence of HARNs confirm the tenets of the FPP, but could be studied by implementating more appropriate toxicological tools for SAR analysis. This includes experimentation with carefully assembled libraries of CNTs and MeNWs, helping to establish more precise dimensional features for interfering in lymphatic drainage from the parietal pleura, triggering of lysosomal damage, frustrated phagocytosis and generation of chronic inflammation. The evidence includes data that long and rigid, but not short and flexible multi-wall CNTs are capable of generating mesotheliomas in rodents based on an adverse outcome pathway requiring access to pleural cavity, obstruction of pleural stomata, chronic inflammation and transformation of mesothelial cells. In addition to durability and dimensional characteristics, bending stiffness of CNTs is a critical factor in determining the shape and rigidity of pathogenic MWCNTs. While no evidence has been obtained in humans that CNT exposure leads to a mesothelioma outcome, it is important to monitor exposure levels and health effect impacts in workers to prevent adverse health outcomes in humans.

The presentations in this session of the Monticello II conference were aimed at summarizing what is known about asbestiform and non-asbestiform elongate mineral particles (EMPs) and mesothelioma risks based on evidence from experimental and epidemiology studies. Dr. Case discussed case reports of mesothelioma over the last several decades. Dr. Taioli indicated that the epidemiology evidence concerning non-asbestiform EMPs is weak or lacking, and that progress would be limited unless mesothelioma registries are established. One exception discussed is that of taconite miners, who are exposed to grunerite. Drs. Mandel and Odo noted that studies of taconite miners in Minnesota have revealed an excess rate of mesothelioma, but the role of non-asbestiform EMPs in this excess incidence of mesothelioma is unclear. Dr. Becich discussed the National Mesothelioma Virtual Bank (NMVB), a virtual mesothelioma patient registry that includes mesothelioma patients' lifetime work histories, exposure histories, biospecimens, proteogenomic information, and imaging data that can be used in epidemiology research on mesothelioma. Dr. Bernstein indicated that there is a strong consensus that long, highly durable respirable asbestiform EMPs have the potential to cause mesothelioma, but there is continued debate concerning the biodurability required, and the dimensions (both length and diameter), the shape, and the dose associated with mesothelioma risk. Finally, Dr. Nel discussed how experimental studies of High Aspect Ratio Engineered Nanomaterials have clarified dimensional and durability features that impact disease risk, the impact of inflammation and oxidative stress on the epigenetic regulation of tumor suppressor genes, and the generation of immune suppressive effects in the mesothelioma tumor microenvironment. The session ended with a discussion of future research needs.

In addition to the contribution of cancer cells, the solid tumor microenvironment (TME) has a critical role in determining tumor expansion, antitumor immunity, and the response to immunotherapy. Understanding the details of the complex interplay between cancer cells and components of the TME provides an unprecedented opportunity to explore combination therapy for intervening in the immune landscape to improve immunotherapy outcome. One approach is the introduction of multifunctional nanocarriers, capable of delivering drug combinations that provide immunogenic stimuli for improvement of tumor antigen presentation, contemporaneous with the delivery of coformulated drug or synthetic molecules that provide immune danger signals or interfere in immune-escape, immune-suppressive, and T-cell exclusion pathways. This forward-looking review will discuss the use of lipid-bilayer-encapsulated liposomes and mesoporous silica nanoparticles for combination immunotherapy of the heterogeneous immune landscapes in pancreatic ductal adenocarcinoma and triple-negative breast cancer. We describe how the combination of remote drug loading and lipid bilayer encapsulation is used for the synthesis of synergistic drug combinations that induce immunogenic cell death, interfere in the PD-1/PD-L1 axis, inhibit the indoleamine-pyrrole 2,3-dioxygenase (IDO-1) immune metabolic pathway, restore spatial access to activated T-cells to the cancer site, or reduce the impact of immunosuppressive stromal components. We show how an integration of current knowledge and future discovery can be used for a rational approach to nanoenabled cancer immunotherapy.

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTWhat Do We Mean When We Say Nanomedicine?Luis M. Liz-MarzánLuis M. Liz-MarzánMore by Luis M. Liz-Marzánhttps://orcid.org/0000-0002-6647-1353, Andre E. NelAndre E. NelMore by Andre E. Nelhttps://orcid.org/0000-0002-5232-4686, C. Jeffrey BrinkerC. Jeffrey BrinkerMore by C. Jeffrey Brinkerhttps://orcid.org/0000-0002-7145-9324, Warren C. W. ChanWarren C. W. ChanMore by Warren C. W. Chanhttps://orcid.org/0000-0001-5435-4785, Chunying ChenChunying ChenMore by Chunying Chenhttps://orcid.org/0000-0002-6027-0315, Xiaodong ChenXiaodong ChenMore by Xiaodong Chenhttps://orcid.org/0000-0002-3312-1664, Dean HoDean HoMore by Dean Hohttps://orcid.org/0000-0002-7337-296X, Tony HuTony HuMore by Tony Huhttps://orcid.org/0000-0002-5166-4937, Kazunori KataokaKazunori KataokaMore by Kazunori Kataokahttps://orcid.org/0000-0002-8591-413X, Nicholas A. KotovNicholas A. KotovMore by Nicholas A. Kotovhttps://orcid.org/0000-0002-6864-5804, Wolfgang J. ParakWolfgang J. ParakMore by Wolfgang J. Parakhttps://orcid.org/0000-0003-1672-6650, and Molly M. StevensMolly M. StevensMore by Molly M. Stevenshttps://orcid.org/0000-0002-7335-266XCite this: ACS Nano 2022, 16, 9, 13257–13259Publication Date (Web):September 27, 2022Publication History Published online27 September 2022Published inissue 27 September 2022https://pubs.acs.org/doi/10.1021/acsnano.2c08675https://doi.org/10.1021/acsnano.2c08675editorialACS PublicationsCopyright © 2022 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views7157Altmetric-Citations6LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (952 KB) Get e-AlertscloseSUBJECTS:Biomaterials,Materials,Nanomaterials,Nanomedicine,Nanoparticles Get e-Alerts

Engineered nanomaterials (ENMs) are commonly used in consumer products, allowing exposure to target organs such as the lung, liver, and skin that could lead to adverse health effects in humans. To better reflect on toxicological effects in liver cells, it is important to consider the contribution of hepatocyte morphology, function, and intercellular interactions in a dynamic 3D microenvironment. Herein, we used a 3D liver spheroid model containing hepatocyte and Kupffer cells (KCs) to study the effects of three different material compositions, namely vanadium pentoxide (V2O5), titanium dioxide (TiO2), or graphene oxide (GO). Additionally, we used single-cell RNA sequencing (scRNAseq) to determine the nanoparticle (NP) and cell-specific toxicological responses. A general finding was that hepatocytes exhibit more variation in gene expression and adaptation of signaling pathways than KCs. TNF-α production tied to the NF-κB pathway was a commonly affected pathway by all NPs while impacts on the metabolic function of hepatocytes were unique to V2O5. V2O5 NPs also showed the largest number of differentially expressed genes in both cell types, many of which are related to pro-inflammatory and apoptotic response pathways. There was also evidence of mitochondrial ROS generation and caspase-1 activation after GO and V2O5 treatment, in association with cytokine production. All considered, this study provides insight into the impact of nanoparticles on gene responses in key liver cell types, providing us with a scRNAseq platform that can be used for high-content screening of nanomaterial impact on the liver, for use in biosafety and biomedical applications.

ADVERTISEMENT RETURN TO ARTICLES ASAPPREVEditorialNEXTTanks and TruthNicholas A. Kotov*Nicholas A. Kotov*Email: [email protected]More by Nicholas A. Kotovhttps://orcid.org/0000-0002-6864-5804, Deji AkinwandeDeji AkinwandeMore by Deji Akinwandehttps://orcid.org/0000-0001-7133-5586, C. Jeffrey BrinkerC. Jeffrey BrinkerMore by C. Jeffrey Brinkerhttps://orcid.org/0000-0002-7145-9324, Jillian M. BuriakJillian M. BuriakMore by Jillian M. Buriakhttps://orcid.org/0000-0002-9567-4328, Warren C. W. ChanWarren C. W. ChanMore by Warren C. W. Chanhttps://orcid.org/0000-0001-5435-4785, Xiaodong ChenXiaodong ChenMore by Xiaodong Chenhttps://orcid.org/0000-0002-3312-1664, Manish ChhowallaManish ChhowallaMore by Manish Chhowallahttps://orcid.org/0000-0002-8183-4044, William ChuehWilliam ChuehMore by William Chuehhttps://orcid.org/0000-0002-7066-3470, Sharon C. GlotzerSharon C. GlotzerMore by Sharon C. Glotzerhttps://orcid.org/0000-0002-7197-0085, Yury GogotsiYury GogotsiMore by Yury Gogotsihttps://orcid.org/0000-0001-9423-4032, Mark C. HersamMark C. HersamMore by Mark C. Hersamhttps://orcid.org/0000-0003-4120-1426, Dean HoDean HoMore by Dean Hohttps://orcid.org/0000-0002-7337-296X, Tony HuTony HuMore by Tony Huhttps://orcid.org/0000-0002-5166-4937, Ali JaveyAli JaveyMore by Ali Javeyhttps://orcid.org/0000-0001-7214-7931, Cherie R. KaganCherie R. KaganMore by Cherie R. Kaganhttps://orcid.org/0000-0001-6540-2009, Kazunori KataokaKazunori KataokaMore by Kazunori Kataokahttps://orcid.org/0000-0002-8591-413X, Il-Doo KimIl-Doo KimMore by Il-Doo Kimhttps://orcid.org/0000-0002-9970-2218, Shuit-Tong LeeShuit-Tong LeeMore by Shuit-Tong Leehttps://orcid.org/0000-0003-1238-9802, Young Hee LeeYoung Hee LeeMore by Young Hee Leehttps://orcid.org/0000-0001-7403-8157, Luis M. Liz-MarzánLuis M. Liz-MarzánMore by Luis M. Liz-Marzánhttps://orcid.org/0000-0002-6647-1353, Jill E. MillstoneJill E. MillstoneMore by Jill E. Millstonehttps://orcid.org/0000-0002-9499-5744, Paul MulvaneyPaul MulvaneyMore by Paul Mulvaneyhttps://orcid.org/0000-0002-8007-3247, Andre E. NelAndre E. NelMore by Andre E. Nelhttps://orcid.org/0000-0002-5232-4686, Peter NordlanderPeter NordlanderMore by Peter Nordlanderhttps://orcid.org/0000-0002-1633-2937, Wolfgang J. ParakWolfgang J. ParakMore by Wolfgang J. Parakhttps://orcid.org/0000-0003-1672-6650, Reginald M. PennerReginald M. PennerMore by Reginald M. Pennerhttps://orcid.org/0000-0003-2831-3028, Andrey L. RogachAndrey L. RogachMore by Andrey L. Rogachhttps://orcid.org/0000-0002-8263-8141, Mathieu SalanneMathieu SalanneMore by Mathieu Salannehttps://orcid.org/0000-0002-1753-491X, Raymond E. SchaakRaymond E. SchaakMore by Raymond E. Schaakhttps://orcid.org/0000-0002-7468-8181, Ajay K. SoodAjay K. SoodMore by Ajay K. Soodhttps://orcid.org/0000-0002-4157-361X, Molly StevensMolly StevensMore by Molly Stevenshttps://orcid.org/0000-0002-7335-266X, Vladimir TsukrukVladimir TsukrukMore by Vladimir Tsukrukhttps://orcid.org/0000-0001-5489-0967, Andrew T. S. WeeAndrew T. S. WeeMore by Andrew T. S. Weehttps://orcid.org/0000-0002-5828-4312, Ilja VoetsIlja VoetsMore by Ilja Voetshttps://orcid.org/0000-0003-3543-4821, Tanja WeilTanja WeilMore by Tanja Weilhttps://orcid.org/0000-0002-5906-7205, and Paul S. WeissPaul S. WeissMore by Paul S. Weisshttps://orcid.org/0000-0001-5527-6248Cite this: ACS Nano 2022, XXXX, XXX, XXX-XXXPublication Date (Web):March 22, 2022Publication History Published online22 March 2022https://doi.org/10.1021/acsnano.2c02602Published 2022 by American Chemical SocietyRIGHTS & PERMISSIONSArticle Views7246Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (998 KB) Get e-Alerts Get e-Alerts

To address the urgent need for safe food allergen immunotherapy, we have developed a liver-targeting nanoparticle platform, capable of intervening in allergic inflammation, mast cell release and anaphylaxis through the generation of regulatory T-cells (Treg). In this communication, we demonstrate the use of a poly (lactide-co-glycolide acid) (PLGA) nanoparticle platform for intervening in peanut anaphylaxis through the encapsulation and delivery of a dominant protein allergen, Ara h 2 and representative T-cell epitopes, to liver sinusoidal endothelial cells (LSECs). These cells have the capacity to act as natural tolerogenic antigen-presenting cells (APC), capable of Treg generation by T-cell epitope presentation by histocompatibility (MHC) type II complexes on the LSEC surface. This allowed us to address the hypothesis that the tolerogenic nanoparticles platform could be used as an effective, safe, and scalable intervention for suppressing anaphylaxis to crude peanut allergen extract. Following the analysis of purified Ara h 2 and representative MHC-II epitopes Treg generation in vivo , a study was carried out to compare the best-performing Ara h 2 T-cell epitope with a purified Ara h 2 allergen, a crude peanut protein extract (CPPE) and a control peptide in an oral sensitization model. Prophylactic as well as post-sensitization administration of the dominant encapsulated Ara h 2 T-cell epitope was more effective than the purified Ara h2 in eliminating anaphylactic manifestations, hypothermia, and mast cell protease release in a frequently used peanut anaphylaxis model. This was accompanied by decreased peanut-specific IgE blood levels and increased TGF-β release in the abdominal cavity. The duration of the prophylactic effect was sustained for two months. These results demonstrate that targeted delivery of carefully selected T-cell epitopes to natural tolerogenic liver APC could serve as an effective platform for the treatment of peanut allergen anaphylaxis.

Effective delivery of activated oxaliplatin to pancreatic cancer achieved by a tailored silicasome nanocarrier is reported by Andre E. Nel, Huan Meng, and co-workers in article number 2005993. This provides a strong immunogenic cell death stimulus that turns the "cold" immunological status into "hot" at tumor site, enabling superior chemo-immunotherapy synergy with anti-PD-1.

There is an urgent need to develop new life-prolonging therapy for pancreatic ductal adenocarcinoma (PDAC). It is demonstrated that improved irinotecan delivery by a lipid bilayer coated mesoporous silica nanoparticle, also known as a silicasome, can improve PDAC survival through a chemo-immunotherapy response in an orthotopic Kras-dependent pancreatic cancer model. This discovery is premised on the weak-basic properties of irinotecan, which neutralizes the acidic lysosomal pH in PDAC cells. This effect triggers a linked downstream cascade of events that include autophagy inhibition, endoplasmic reticulum stress, immunogenic cell death (ICD), and programmed death-ligand 1 (PD-L1) expression. ICD is characterized by calreticulin expression and high-mobility group box 1 (HMGB1) release in dying Kras-induced pancreatic cancer (KPC) cells, which is demonstrated in a vaccination experiment to prevent KPC tumor growth on the contralateral site. The improved delivery of irinotecan by the silicasome is accompanied by robust antitumor immunity, which can be synergistically enhanced by anti-PD-1 in the orthotopic model. Immunophenotyping confirms the expression of calreticulin, HMGB1, PD-L1, and an autophagy marker, in addition to perforin and granzyme B deposition. The chemo-immunotherapy response elicited by the silicasome is more robust than free or a liposomal drug, Onivyde. The silicasome plus anti-PD-1 leads to significantly enhanced survival improvement, and is far superior to anti-PD-1 plus either free irinotecan or Onivyde.

In this study a mesoporous silica nanoparticle (MSNP) based platform is developed for high-dose loading of a range of activated platinum (Pt) chemo agents that can be attached to the porous interior through the use of electrostatic and coordination chemistry under weak-basic pH conditions. In addition to the design feature for improving drug delivery, the MSNP can also be encapsulated in a coated lipid bilayer (silicasome), to improve the colloidal stability after intravenous (IV) injection. Improved pharmacokinetics and intratumor delivery of encapsulated activated oxaliplatin (1,2-diamminocyclohexane platinum(II) (DACHPt)) over free drug in an orthotopic Kras-derived pancreatic cancer (PDAC) model is demonstrated. Not only does IV injection of the DACHPt silicasome provide more efficacious cytotoxic tumor cell killing, but can also demonstrate that chemotherapy-induced cell death is accompanied by the features of immunogenic cell death (ICD) as well as a dramatic reduction in bone marrow toxicity. The added ICD features are reflected by calreticulin and high-mobility group box 1 expression, along with increased CD8+ /FoxP3+ T-cell ratios and evidence of perforin and granzyme B release at the tumor site. Subsequent performance of a survival experiment, demonstrates that the DACHPt silicasome generates a significant improvement in survival outcome, which can be extended by delayed administration of the anti-PD-1 antibody.