Molecular Polymer Bottlebrushes for Nanomedicine: Structure-Guided Design, Biological Transport, and Biomedical Applications

Abstract

Molecular polymer bottlebrushes (MPBs) are structurally programmable macromolecules whose densely grafted side chains generate stable unimolecular architectures with tunable structural features. Despite growing interest in MPBs for nanomedicine, the relationships between their architectural parameters and biological performance have not yet been systematically integrated. This review, therefore, aims to establish a structure-centered framework that links MPB architecture to biological behavior and design requirements in nanomedicine. We first summarize the principal structural parameters and major synthetic strategies of MPBs, and then discuss how size and aspect ratio, stiffness, grafting density, topology, and surface chemistry influence their biological behavior. Representative applications in small-molecule drug and nucleic-acid delivery, bioimaging, and theranostics illustrate how the structure–behavior relationships translate into functional outcomes. The available evidence is further integrated into an outcome-oriented design framework that considers stage-specific requirements across systemic circulation, tissue access, cellular interaction, intracellular release, and clearance. In addition, selected bottlebrush-derived nanostructures are considered separately from unimolecular MPBs. Current challenges in scalable and reproducible synthesis, degradability, long-term safety and clearance, and computationally assisted design are also discussed. Overall, this review offers a structure-centered perspective for understanding and designing MPB-based nanomedicine platforms tailored to complex biological environments.