Nanoengineering Apolipoprotein A1‐Based Immunotherapeutics

Abstract

In the slipstream of targeting the adaptive immune system, innate immunotherapy strategies are being developed. In this context, technologies based on natural carrier vehicles that inherently interact with the innate immune system, are increasingly being considered. Immunoregulatory nanotherapeutics based on natural apolipoprotein A1 (apoA1) are discussed here. This protein is a helical, amphipathic macromolecule and the main constituent of high-density lipoprotein. In that capacity, apoA1 interacts specifically with innate immune cells, such as monocytes and macrophages, to collect and transport lipophilic molecules throughout the body. Exactly these unique features make apoA1 a compelling elementary constituent of biocompatible self-assembled nanotherapeutics. Such apoA1-based nanotherapeutics (A1-nanotherapeutics) can be engineered and functionalized to induce or mitigate an innate immune response or to orchestrate an adaptive immune response through antigen delivery to dendritic cells. The authors first discuss apoA1's properties and how these can be exploited to generate libraries of A1-nanotherapeutics using advanced manufacturing approaches such as microfluidics or continuous flow methods. Using high-throughput in vitro screening methods and in vivo imaging to identify promising formulations are then recommend. Finally, three distinct immunotherapy strategies are proposed to effectively treat a variety of diseases-including cancer, infection, and cardiovascular disease-and promote allograft survival in transplantation.

Human airway macrophages are metabolically reprogrammed by IFN-γ resulting in glycolysis dependent functional plasticity

“…Trained immunity improves innate responses to infection and is emerging as a key component of host directed therapies (HDT) and strategies to improve vaccine efficacy and the design of respiratory mucosal vaccines (26,27,(37)(38)(39). Both IFN-γ and IL-4 can induce trained immunity in murine and human macrophages (12,19,40,41). MDM trained with IFN-γ and LPS, and stimulated with Mtb had increased TNF in the acute activation phase of trained immunity (19), which we observed in IFN-γ primed MDM subsequently stimulated with Mtb.…”

Trained immunity: Target for prophylaxis and therapy

“…179 These high-density lipoprotein (HDL)-inspired nanoparticles are well-tolerated after systemic administration as they consist of natural materials such as (phospho)lipids and include apolipoprotein A1 (apoA1) for structural integrity and myeloid cell interactions. 180 Moreover, the modular platform nanotechnology can be bioengineered to contain a range of therapeutics to regulate trained immunity. 178 In a compelling example of promoting trained immunity for cancer treatment, Priem et al developed nanobiologics that were surface functionalized with the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) receptor agonist muramyldipeptide (MDP).…”

A Current Update on the Role of HDL-Based Nanomedicine in Targeting Macrophages in Cardiovascular Disease

“…The three-dimensional structure of ApoA-I bound to phospholipids has been thoroughly explored [ 74 ]. The structural properties of ApoA-I are harnessed in the synthesis of HDL nanotherapeutics as a naturally available blue print for design [ 75 , 76 ]. Apart from offering structural advantages to HDL nanoparticles as a scaffold for stability, HDL-associated ApoA-I is responsible for a majority of anti-inflammatory and atheroprotective properties of HDL, especially in promoting cholesterol efflux and preventing the migration of monocytes to the inflamed endothelia [ 77 , 78 , 79 , 80 , 81 ].…”