Targeted modulation of immune cells and tissues using engineered biomaterials

Abstract

system. We focus on approaches targeting immune cells and lymphoid organs, excluding direct targeting of pathogens such as viruses or bacteria, followed by a discussion on prospects and challenges for developments in this area. Targeting lymphoid organsLymphoid organs coordinate the maturation and migration of immune cells while organizing and regulating immune responses (Fig. 1a). Primary lymphoid organs in adults include the bone marrow and thymus, which serve as niches for lymphocyte development. Secondary lymphoid organs -which include 600-800 lymph nodes distributed across the body, the spleen and the mucosa-associated lymphoid tissue -house and organize T cells, B cells and antigen-presenting cells (APCs). These organs serve as command centres of adaptive immunity where activation of naive B and T lymphocytes occurs (Fig. 1a,b) and are thus natural targets for vaccines and immunotherapies. Principles of lymph node targetingPassive targeting of therapeutics to lymphatic vessels. Lymph nodes interface with peripheral tissues through lymphatic vessels, which drain lymph fluid from all tissues and provide a conduit for immune cell trafficking. Drugs and vaccines can be targeted to lymph nodes through lymphatic uptake following parenteral injection. A major factor influencing lymphatic targeting is the physical size of the injected agents: following injection into tissue (including tumours), particles larger than 50-100 nm in diameter become trapped in the extracellular matrix (ECM), whereas particles in the size range of 5-50 nm convect with lymph into the lymphatic vessels and flow to draining lymph nodes (dLNs). By contrast, particles smaller than 5 nm partition preferentially into the blood rather than the lymph 9,10 (Fig. 2a). These approximate size ranges depend on the tissue site of injection (which can vary in ECM and lymphatic composition) and factors such as injection volume and rate (which can cause mechanical expansion of the flaps mediating entry into lymphatic vessels), especially in small-animal models, where tissue volume relative to injection volume is much smaller. Furthermore, particle shape, charge and surface chemistry can also play a part by promoting or hindering convection through the tissue and lymphatic entry 11 . Notably, capture of particles at the downstream dLN is a less studied but equally important prerequisite for lymph node modulation, as evidenced by data showing that proteins 12 and small hydrophilic nanoparticles 13 can pass through the entire lymphatic chain, reach the thoracic duct and enter the systemic circulation following a parenteral injection. In this regard, using adjuvants that promote compound entry into lymph nodes 14 , or designing carriers that stimulate recognition by macrophages lining the subcapsular and medullary sinuses, can prove useful 15 .Protein nanoparticles with surface-arrayed antigens and a size optimized for efficient lymphatic uptake enhance the immunogenicity of vaccines [16][17][18][19][20] . Protein nanoparticle vaccines are currently in clinic...

Biomaterials for in situ cell therapy

“…[85] Because DCs derived from patients require activation ex vivo before injection into the body, challenges have severely hindered the widespread clinical utilization of DC-based cell therapy, including the poor homing efficiency, with less than 5% arriving at the draining lymph nodes, [71] low response rates, [86] high development costs and manufacturing. [86][87][88] In situ activation of DC is the optimal protocol for maximizing DC cell therapy. Biomaterials with adjustable physicochemical properties and optimized release kinetics provide practical strategies to deliver antigens, adjuvants, or nucleic acid to DC cells in vivo.…”

“…Biomaterials with adjustable physicochemical properties and optimized release kinetics provide practical strategies to deliver antigens, adjuvants, or nucleic acid to DC cells in vivo. [87,89] In the early 1990s, Martinon et al utilized non-viral liposomes to deliver mRNA-encoding antigens into DCs to stimulate virus-specific cytotoxic T lymphocytes (CTLs) in vivo. [90] In 2016, Katakowski et al functionalized LNPs with an scFv that specifically targets murine DEC205 in vivo, a surface marker prominently expressed on CD8α + DCs.…”

“…To date, one DC cell therapy product, Provenge®, has granted approval by the FDA for treating metastatic castrate‐resistant prostate cancer [85] . Because DCs derived from patients require activation ex vivo before injection into the body, challenges have severely hindered the widespread clinical utilization of DC‐based cell therapy, including the poor homing efficiency, with less than 5% arriving at the draining lymph nodes, [71] low response rates, [86] high development costs and manufacturing [86–88] . In situ activation of DC is the optimal protocol for maximizing DC cell therapy.…”

“…In situ activation of DC is the optimal protocol for maximizing DC cell therapy. Biomaterials with adjustable physicochemical properties and optimized release kinetics provide practical strategies to deliver antigens, adjuvants, or nucleic acid to DC cells in vivo [87,89] …”

Protein-Decorated Microbubbles for Ultrasound-Mediated Cell Surface Manipulation

“…This is partly because this type of adaptive therapy requires complex ex vivo procedures. A method to overcome this bottleneck would be highly beneficial for targeted therapies, and there is an increasing interest in the development of therapies capable of modulating the immune system in vivo, including biomaterials-based strategies . This work demonstrates a potential method to manipulate the cell surface using microbubbles (MBs) and ultrasound (US).…”