Cellulose- and lignin-based smart hydrogels for barrier-adaptive delivery of fragile biotherapeutics: Molecular design, activity preservation, and translational considerations.

Abstract

Fragile biotherapeutics-including therapeutic proteins, peptides, antibody fragments, nucleic acids, and extracellular-vesicle therapeutics-are increasingly central to precision medicine, yet their delivery is limited by conformational instability, enzymatic degradation, oxidative damage, interfacial adsorption, and poor transport across biological barriers. Cellulose- and lignin-based smart hydrogels offer a renewable and chemically versatile platform for addressing these limitations. Within these systems, cellulose primarily governs hydration, swelling, mesh size, mechanical integrity, and diffusion, whereas lignin provides aromatic and phenolic domains that may confer antioxidant, antibacterial, and redox-modulating functions. This review critically assesses cellulose-, lignin-, and other natural-macromolecule-based hydrogels from a payload-centered, barrier-adaptive perspective. Representative systems are compared by composition, crosslinking chemistry, stimulus responsiveness, payload class, encapsulation and release behavior, activity retention, barrier-model validation, in vivo performance, and translational constraints. Particular attention is given to the distinction between model compounds and authentic biotherapeutics, because high encapsulation efficiency and favorable cumulative release do not, by themselves, establish functional delivery. We evaluate the utility and limitations of pH-, enzyme-, redox-, temperature-, and light-responsive mechanisms in gastrointestinal, tumor, wound/skin, and central-nervous-system applications. Where available, quantitative evidence on release, degradation, rheology, activity retention, biodistribution, and therapeutic efficacy is highlighted. Finally, we propose a translational evidence framework that links raw-material identity and network transformation to payload integrity, biological activity, safety, manufacturability, sterilization, storage stability, quality control, and regulatory readiness. This framework provides practical guidance for advancing cellulose- and lignin-based hydrogels from responsive materials to function-preserving, translatable delivery systems for fragile biotherapeutics.