A Review on Lymphatic Uptake of Large Therapeutic Proteins after Subcutaneous Injection

Subcutaneous (SC) administration has emerged as a promising route for delivering large therapeutic proteins, offering advantages such as improved patient convenience and reduced healthcare costs. However, the mechanisms that regulate the uptake of these macromolecules are not yet fully understood. A recent surge in computational and experimental studies has systematically analyzed the transport of large proteins from the SC injection site to the lymphatic system, advancing our understanding of how tissue environments and injection parameters affect lymphatic uptake kinetics. This review summarizes the current literature on factors affecting the lymphatic uptake of subcutaneously administered large therapeutic proteins. First, we outline the transport mechanisms of therapeutic proteins from the local SC injection site to initial lymphatics. Then we analyze the impact of injection site, tissue properties, device selection, and molecular characteristics, on lymphatic uptake kinetics and pharmacokinetics (PK). Finally, we evaluate how recent modeling and experimental advancements have transformed our mechanistic understanding of SC delivery.