NETosis induction reflects COVID-19 severity and long COVID: insights from a 2-center patient cohort study in Israel.

BACKGROUND: COVID-19 severity and its late complications continue to be poorly understood. Neutrophil extracellular traps (NETs) form in acute COVID-19, likely contributing to morbidity and mortality. OBJECTIVES: This study evaluated immunothrombosis markers in a comprehensive cohort of acute and recovered COVID-19 patients, including the association of NETs with long COVID. METHODS: One-hundred-seventy-seven patients were recruited from clinical cohorts at 2 Israeli centers: acute COVID-19 (mild/moderate, severe/critical), convalescent COVID-19 (recovered and long COVID), along with 54 non-COVID controls. Plasma was examined for markers of platelet activation, coagulation, and NETs. Ex vivo NETosis induction capability was evaluated after neutrophil incubation with patient plasma. RESULTS: Soluble P-selectin, factor VIII, von Willebrand factor, and platelet factor 4 were significantly elevated in patients with COVID-19 versus controls. Myeloperoxidase (MPO)-DNA complex levels were increased only in severe COVID-19 and did not differentiate between COVID-19 severities or correlate with thrombotic markers. NETosis induction levels strongly correlated with illness severity/duration, platelet activation markers, and coagulation factors, and were significantly reduced upon dexamethasone treatment and recovery. Patients with long COVID maintained higher NETosis induction, but not NET fragments, compared to recovered convalescent patients. CONCLUSIONS: Increased NETosis induction can be detected in patients with long COVID. NETosis induction appears to be a more sensitive NET measurement than MPO-DNA levels in COVID-19, differentiating between disease severity and patients with long COVID. Ongoing NETosis induction capability in long COVID may provide insights into pathogenesis and serve as a surrogate marker for persistent pathology. This study emphasizes the need to explore neutrophil-targeted therapies in acute and chronic COVID-19.

Mucoadhesive Hybrid Polymer/Liposome Pastes Based on Modified Polysaccharides.

Mucoadhesive hybrid polymer/liposome paste is a new drug delivery system presenting controllable and tailorable delivery mechanism. By using mucoadhesive material, the delivery can be more specific and local. Here, we present a study investigating the effect of polymer type, concentration, functional end group, and cross-linking on the release profile of nanoliposomes from polymer pastes. Polymer pastes can be expected to combine the mucoadhesion mechanisms of dry and wet dosage forms but have not been studied extensively. To better understand the mucoadhesion of pastes, we investigated a series of pastes based on the same polymer and used different chemical modifications that can produce interactions at different levels. Native and thiolated polymers presented enhanced mucoadhesion in a wet environment in comparison to acrylated polymers which dissolved rapidly because of the enhanced solubility of PEG chains in water. Paste cross-linking resulted in a sustained release profile compared to non-cross-linked pastes. Pectin-SH pastes, especially 3% (w/v), showed a linear liposomal release profile which is ascribed to the combination of ionic cross-linking and disulfide bridging. By configuring the polymer type or concentration, we can control the release mechanisms and achieve distinct inherent properties which can be applied for diverse medical applications.

Mucoadhesive alginate pastes with embedded liposomes for local oral drug delivery.

Oral cancers are extremely common among adults with increasing incidences due to human papillomavirus, while treatment modalities are limited. This study aims to develop a new oral mucoadhesive delivery system based on the combination of alginate and liposomes. The polymer provides adhesion properties and induces local release of the drug-loaded carriers, while the liposomes protect the drug from degradation and improve its absorption into the cells. Three hybrid alginate/liposomes delivery systems were investigated: a hybrid paste, which presented excellent adhesive capabilities, yet fast burst release of 90% after 2h; a hybrid hydrogel, demonstrating controllable release rates of 5%, 30% or 60% after 2h but poor mucoadhesive properties. These findings led to the development of a hybrid cross-linked paste. Polymer retention studies demonstrated that 80% of the crosslinked paste was retained on tongue tissue compared to 50% retention of the non-cross-linked pastes, verifying its superior mucoadhesion. The hybrid cross-linked paste presented controllable release rate of 20% after 2h. Alginate paste incorporating doxorubicin loaded liposomes presented similar release rates and were highly effective in promoting cancer cell death. Thus, our innovative formulation, including both desired characteristics of mucoadhesion and sustained liposomes release, is an important milestone in the development of a new potential treatment for oral cancer.