Innate and adaptive immune responses toward nanomedicines

Abstract

Since the commercialization of the first liposomes used for drug delivery, Doxil/Caelyx® and Myocet®, tremendous progress has been made in understanding interactions between nanomedicines and biological systems. Fundamental work at the interface of engineering and medicine has allowed nanomedicines to deliver therapeutic small molecules and nucleic acids more efficiently. While nanomedicines are used in oncology for immunotherapy or to deliver combinations of cytotoxics, the clinical successes of gene silencing approaches like patisiran lipid complexes (Onpattro®) have paved the way for a variety of therapies beyond cancer. In parallel, the global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has highlighted the potential of mRNA vaccines to develop immunization strategies at unprecedented speed. To rationally design therapeutic and vaccines, chemists, materials scientists, and drug delivery experts need to better understand how nanotechnologies interact with the immune system. This review presents a comprehensive overview of the innate and adaptative immune systems and emphasizes the intricate mechanisms through which nanomedicines interact with these biological functions.

Keywords: Anti-PEG antibody; BNT162b2; Cancer immunotherapy; Complement activation; Immunology; In vivo clearance; Macrophage; Nanoparticle; mRNA vaccine; mRNA-1273.

Graphical abstract

Figure 1

Leukocytes originate from hematopoietic stem cells in the bone marrow. Stem cells give rise to lymphoid and myeloid cells, which are common progenitors of leukocytes and other blood cells. Monocytes (the precursor of macrophages), mast cells and granulocytes (basophils, neutrophils, and eosinophils) originate from myeloid cells. Lymphoid cells produce B- and T-lymphocytes and natural killer cells. Dendritic cells can originate from monocytes or lymphoid precursors. All leukocytes exhibit the CD45 protein on their surface. Common receptors for each cell type in mice (M) and humans (H) are presented in red (both M/H), green (only H) or black (only M). According to their main function in the immune system, leukocytes can be subdivided in adaptive cells (left) or innate cells (right).

Figure 2

Phagocytes have different types of receptors enabling phagocytosis. Pattern receptors directly recognize molecules on the surface of pathogens. Opsonic receptors recognize changes in conformation of soluble proteins when the latter bind to a pathogen. Apoptotic corpse receptors recognize extracellular exposure of phosphatidylserine on the surface of dying cells.

Figure 3

The complement cascade can be initiated by the alternative, classical, or lectin pathways (A). Independently of the pathway, the binding of C6, C7, C8, and C9 proteins to the C5b protein leads to formation of C5b9, also known as terminal complement complex (B).

Figure 4

Leukocytes and antigens travel through the blood and the lymph. The lymph is a mix of extracellular fluids and leukocytes drained from tissues of the entire body. The lymph flows from tissues to lymph nodes, reentering the venous circulation through the thoracic duct. Adaptative immune response results from the encounters between antigens and leukocytes.

Figure 5

Nanomedicines can impact the field of cancer immunotherapy and prompt the immune system to fight tumors more efficiently.