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The gastrointestinal tract (GIT) affects not only local diseases in the GIT but also various systemic diseases. Factors that can affect the health and disease of both GIT and the ...human body include 1) the mucosal immune system composed of the gut-associated lymphoid tissues and the lamina propria, 2) the intestinal barrier composed of mucus and intestinal epithelium, and 3) the gut microbiota. Selective delivery of drugs, including antigens, immune-modulators, intestinal barrier enhancers, and gut-microbiome manipulators, has shown promising results for oral vaccines, immune tolerance, treatment of inflammatory bowel diseases, and other systemic diseases, including cancer. However, physicochemical and biological barriers of the GIT present significant challenges for successful translation. With the advances of novel nanomaterials, oral nanomedicine has emerged as an attractive option to not only overcome these barriers but also to selectively deliver drugs to the target sites in GIT. In this review, we discuss the GIT factors and physicochemical and biological barriers in the GIT. Furthermore, we present the recent progress of oral nanomedicine for oral vaccines, immune tolerance, and anti-inflammation therapies. We also discuss recent advances in oral nanomedicine designed to fortify the intestinal barrier functions and modulate the gut microbiota and microbial metabolites. Finally, we opine about the future directions of oral nano-immunotherapy.
Abstract
Background
Troponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to ...assess myocardial injury in recovered COVID-19 patients.
Methods and results
One hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection all requiring hospital admission, 48 (32%) requiring ventilatory support and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms).
Conclusions
During convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected.
Graphical Abstract
Recent studies have demonstrated great therapeutic potential of educating and unleashing our own immune system for cancer treatment. However, there are still major challenges in cancer immunotherapy, ...including poor immunogenicity of cancer vaccines, off-target side effects of immunotherapeutics, as well as suboptimal outcomes of adoptive T cell transfer-based therapies. Nanomaterials with defined physico-biochemical properties are versatile drug delivery platforms that may address these key technical challenges facing cancer vaccines and immunotherapy. Nanoparticle systems have been shown to improve targeted delivery of tumor antigens and therapeutics against immune checkpoint molecules, amplify immune activation via the use of new stimuli-responsive or immunostimulatory materials, and augment the efficacy of adoptive cell therapies. Here, we review the current state-of-the-art in nanoparticle-based strategies designed to potentiate cancer immunotherapies, including cancer vaccines with subunit antigens (e.g., oncoproteins, mutated neo-antigens, DNA and mRNA antigens) and whole-cell tumor antigens, dendritic cell-based vaccines, artificial antigen-presenting cells, and immunotherapeutics based on immunogenic cell death, immune checkpoint blockade, and adoptive T-cell therapy.
While conventional approaches for inflammatory bowel diseases mainly focus on suppressing hyperactive immune responses, it remains unclear how to address disrupted intestinal barriers, dysbiosis of ...the gut commensal microbiota and dysregulated mucosal immune responses in inflammatory bowel diseases. Moreover, immunosuppressive agents can cause off-target systemic side effects and complications. Here, we report the development of hyaluronic acid-bilirubin nanomedicine (HABN) that accumulates in inflamed colonic epithelium and restores the epithelium barriers in a murine model of acute colitis. Surprisingly, HABN also modulates the gut microbiota, increasing the overall richness and diversity and markedly augmenting the abundance of Akkermansia muciniphila and Clostridium XIVα, which are microorganisms with crucial roles in gut homeostasis. Importantly, HABN associated with pro-inflammatory macrophages, regulated innate immune responses and exerted potent therapeutic efficacy against colitis. Our work sheds light on the impact of nanotherapeutics on gut homeostasis, microbiome and innate immune responses for the treatment of inflammatory diseases.
Photothermal therapy (PTT) is a promising cancer treatment modality, but PTT generally requires direct access to the source of light irradiation, thus precluding its utility against disseminated, ...metastatic tumors. Here, we demonstrate that PTT combined with chemotherapy can trigger potent anti-tumor immunity against disseminated tumors. Specifically, we have developed polydopamine-coated spiky gold nanoparticles as a new photothermal agent with extensive photothermal stability and efficiency. Strikingly, a single round of PTT combined with a sub-therapeutic dose of doxorubicin can elicit robust anti-tumor immune responses and eliminate local as well as untreated, distant tumors in >85% of animals bearing CT26 colon carcinoma. We also demonstrate their therapeutic efficacy against TC-1 submucosa-lung metastasis, a highly aggressive model for advanced head and neck squamous cell carcinoma (HNSCC). Our study sheds new light on a previously unrecognized, immunological facet of chemo-photothermal therapy and may lead to new therapeutic strategies against advanced cancer.
The immune system has evolved over time to protect the host from foreign microorganisms. Activation of the immune system is predicated on a distinction between self and nonself. Unfortunately, cancer ...is characterized by genetic alterations in the host's cells, leading to uncontrolled cellular proliferation and evasion of immune surveillance. Cancer immunotherapy aims to educate the host's immune system to not only recognize but also attack and kill mutated cancer cells. While immune checkpoint blockers have been proven to be effective against multiple types of advanced cancer, the overall patient response rate still remains below 30%. Therefore, there is an urgent need to improve current cancer immunotherapies. In this Account, we present an overview of our recent progress on nanoparticle-based strategies for improving cancer vaccines and immunotherapies. We also present other complementary strategies to give a well-rounded snapshot of the field of combination cancer immunotherapy. The versatility and tunability of nanoparticles make them promising platforms for addressing individual challenges posed by various cancers. For example, nanoparticles can deliver cargo materials to specific cells, such as vaccines delivered to antigen-presenting cells for strong immune activation. Nanoparticles also allow for stimuli-responsive delivery of various therapeutics to cancer cells, thus forming the basis for combination cancer immunotherapy. Here, we focus on nanoparticle platforms engineered to deliver tumor antigens, whole tumor cells, and chemotherapeutic or phototherapeutic agents in a manner to effectively and safely trigger the host's immune system against tumor cells. For each work, we discuss the nanoparticle platform developed, synthesis chemistry, and in vivo applications. Nanovaccines offer a unique platform for codelivery of personalized tumor neoantigens and adjuvants and elicitation of robust immune responses against aggressive tumors. Nanovaccines either delivering whole tumor cell lysate or formed from tumor cell lysate may increase the repertoire of tumor antigens as immune targets while exploiting immunogenic cell death to prime antitumor immune responses. We also discuss how antigen- and whole tumor cell-based approaches may open the door for personalized cancer vaccination and immunotherapy. On the other hand, chemotherapy, phototherapy, and radiotherapy are more standardized cancer therapies, and nanoparticle-based approaches may promote their ability to initiate T cell activation against tumor cells and improve antitumor efficacy with minimal toxicity. Finally, building on the recent progress in nanoparticle-based cancer immunotherapy, the field should set the ultimate goal to be clinical translation and clinical efficacy. We will discuss regulatory, analytical, and manufacturing hurdles that should be addressed to expedite the clinical translation of nanomedicine-based cancer immunotherapy.
Rapid vaccine-induced population immunity is a key global strategy to control COVID-19. Vaccination programmes must maximise early impact, particularly with accelerated spread of new variants.1 Most ...vaccine platforms use a two-dose prime-boost approach to generate an immune response against the virus S1 spike protein, the titres of which correlate with functional virus neutralisation and increase with boosting.2,3 To enable larger numbers of people to receive the first dose, delayed administration of the second dose has been advocated and implemented by some.1 The impact of previous SARS-CoV-2 infection on the need for boosting is not known. To test this, we undertook a nested case-control analysis of 51 participants of COVIDsortium,4,5 an ongoing longitudinal observational study of health-care workers (HCWs) in London who underwent weekly PCR and quantitative serology testing from the day of the first UK lockdown on March 23, 2020, and for 16 weeks onwards. 24 of 51 HCWs had a previous laboratory-confirmed mild or asymptomatic SARS-CoV-2 infection, as confirmed by positive detection of antibodies against the SARS-CoV-2 nucleocapsid (Elecsys Anti-SARS-CoV-2 N ECLIA, Roche Diagnostics, Burgess Hill, UK) or the receptor binding domain of the SARS-CoV-2 S1 subunit of the spike protein (anti-S; Elecsys anti-SARS-CoV-2 spike ECLIA, Roche Diagnostics), whereas 27 HCWs remained seronegative.
The novel corona virus termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread throughout the globe at a formidable speed, causing tens of millions of cases and more than one ...million deaths in less than a year of its report in December 2019. Since then, companies and research institutions have raced to develop SARS-CoV-2 vaccines, ranging from conventional viral and protein-based vaccines to those that are more cutting edge, including DNA- and mRNA-based vaccines. Each vaccine exhibits a different potency and duration of efficacy, as determined by the antigen design, adjuvant molecules, vaccine delivery platforms, and immunization method. In this review, we will introduce a few of the leading non-viral vaccines that are under clinical stage development and discuss delivery strategies to improve vaccine efficacy, duration of protection, safety, and mass vaccination.
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