Abstract: Natural endogenous materials (NEMs), such as cell and cell derivatives, polysaccharide, protein and peptide, and nucleic acid-derived vectors, often exhibit biocompatibility, biodegradability and natural homing ability, which can minimize adverse reactions in vivo and have the potential to improve drug delivery efficacy. Currently, a variety of drug delivery systems (DDSs) based on NEMs have been constructed for macromolecules to address the challenges posed by their inherent large size, intricate structure, low permeability, and susceptibility to harsh environments. The aim of this article is to provide a comprehensive overview of various delivery strategies that predominantly utilize NEMs as carriers for macromolecular delivery. By thoroughly discussing the pros and cons of NEM-based DDSs, we hope to provide valuable insights into future innovations in pharmaceutical science, with a focus on improving therapeutic outcomes through advanced drug formulations.