Developing bioinspired delivery systems for enhanced tumor penetration of macromolecular drugs

Macromolecular drugs, such as proteins and nucleic acids, play a pivotal role in treating refractory diseases and hold significant promise in the growing pharmaceutical market. However, without efficient delivery systems, macromolecular drugs are highly susceptible to rapid biodegradation or systemic clearance, underscoring the need for advanced delivery strategies for clinical translation. A major challenge lies in their limited tissue penetration due to large molecular weight and size, which has recently garnered significant attention as it often leads to therapeutic failure or the emergence of resistance. In this review, we first outline the biological barriers limiting macromolecular tissue penetration, then explore the inherent permeation mechanisms of biomacromolecules in biological systems. We then highlight delivery strategies aimed at enhancing the tissue penetration of macromolecular therapeutics, with a particular focus on tissue-adaptive and tissue-remodeling delivery platforms. Finally, we provide a concise perspective on future research directions in deep tissue penetration for biomacromolecules. This review offers a comprehensive summary of recent advancements and presents critical insights into optimizing the therapeutic efficacy of macromolecular drugs.