The article discusses the advancements in targeted drug delivery systems that utilize endocytosis, a cellular process where macromolecules are internalized and transported through the endolysosomal pathway. Endocytosis is a common mechanism in all cells, allowing the internalization of macromolecules and their retention in transport vesicles. The review highlights the importance of understanding the key players in different vesicular internalization mechanisms, such as clathrin-dependent and clathrin-independent endocytosis, to engineer macromolecular complexes for specialized delivery. The article emphasizes the clinical significance of targeted drug delivery to endolysosomal systems, particularly in treating lysosomal storage diseases, Alzheimer's disease, and cancer. It also explores the use of receptor-mediated endocytosis (RME) and fluid phase endocytosis (FPE) for targeted delivery, and the potential of nanoscale carriers in improving drug delivery efficiency. The review concludes by discussing the challenges and future directions in the field, including the need for further research on receptor regulation and the development of synthetic receptor approaches for high-affinity binding.The article discusses the advancements in targeted drug delivery systems that utilize endocytosis, a cellular process where macromolecules are internalized and transported through the endolysosomal pathway. Endocytosis is a common mechanism in all cells, allowing the internalization of macromolecules and their retention in transport vesicles. The review highlights the importance of understanding the key players in different vesicular internalization mechanisms, such as clathrin-dependent and clathrin-independent endocytosis, to engineer macromolecular complexes for specialized delivery. The article emphasizes the clinical significance of targeted drug delivery to endolysosomal systems, particularly in treating lysosomal storage diseases, Alzheimer's disease, and cancer. It also explores the use of receptor-mediated endocytosis (RME) and fluid phase endocytosis (FPE) for targeted delivery, and the potential of nanoscale carriers in improving drug delivery efficiency. The review concludes by discussing the challenges and future directions in the field, including the need for further research on receptor regulation and the development of synthetic receptor approaches for high-affinity binding.