Engineering Biomacromolecules for Advanced Drug Delivery Through Structure–Function Relationships

Biomacromolecules have emerged as versatile building blocks for advanced drug delivery systems owing to their biocompatibility, biodegradability, chemical functionality, molecular recognition, and capacity for hierarchical organization. However, their delivery performance is governed not simply by material identity but by complex relationships between molecular structure and functional behavior. This review provides a structure–function-oriented overview of biomacromolecular drug delivery, encompassing polysaccharides, proteins and polypeptides, peptides, and nucleic acid-based materials. Particular emphasis is placed on key molecular determinants, including molecular weight and chain architecture, charge and functional groups, hydrophobicity and amphiphilicity, molecular conformation, intermolecular interactions, and biodegradability. We further discuss how chemical modification, crosslinking, self-assembly, targeting, and stimuli-responsive engineering translate these molecular features into functional delivery architectures, including nanoparticles, micelles, nanogels, hydrogels, fibrous matrices, and hybrid systems. The influence of biomacromolecular structure on drug loading, encapsulation, controlled release, protein adsorption, mucosal interactions, cellular uptake, intracellular trafficking, biodistribution, and biocompatibility is critically examined. Representative applications in cancer therapy, nucleic acid delivery, protein and peptide delivery, anti-inflammatory treatment, regenerative medicine, and localized delivery are also highlighted. Finally, current challenges associated with structural heterogeneity, batch-to-batch variability, stability, safety, scale-up, and manufacturing are discussed. Future integration of advanced characterization, molecular modeling, Quality-by-Design, and artificial intelligence/machine learning may enable a transition from empirical formulation toward predictive biomacromolecular engineering. Establishing quantitative links across molecular structure, material properties, carrier architecture, biological interactions, and therapeutic performance will be essential for the rational design and clinical translation of next-generation biomacromolecular drug delivery systems.