Nanolignin: A Natural Drug Delivery System

Native lignin is an aromatic polymer characterized by abundant reserves, inherent renewability, and favorable biocompatibility. Its nanoscale derivatives, particularly nanolignin, have attracted significant attention in drug delivery research. The lignin molecular skeleton is rich in reactive functional groups, which not only serve as a structural foundation for drug loading but also offer versatile sites for functional modification. Through precise chemical modification of these active sites, environment-responsive moieties can be introduced into the nanolignin matrix, endowing it with smart stimuli-responsive capabilities and facilitating its transition from a simple structural carrier to an intelligent drug delivery platform. In contrast to previous reports, this review begins by systematically summarizing the structural basis and drug loading mechanisms of nanolignin in drug delivery. It then categorizes and discusses how various modification strategies, including pH-sensitive, gas-sensitive, thermosensitive, and enzyme-sensitive approaches, affect the controlled release behavior of drugs. Empirical studies have shown that functionalized nanolignin combines outstanding biocompatibility with high drug encapsulation efficiency and targeted delivery, thereby preserving the therapeutic efficacy of the encapsulated drugs while significantly reducing off-target toxicity. Finally, given the key challenges currently confronting the field, including the limited range of stimuli-responsive modes and the weak synergy in multi-stimuli-responsive systems, this review offers insights into the future direction of nanolignin-based smart drug delivery systems. It aims to serve as a reference for the rational design of effective, safe, and sustainable lignin-based nanocarriers.