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This study introduces a biocompatible, stimuli-responsive theranostic system with ultrasmall iron oxide nanoparticles (USPIONs) encapsulated within the hyaluronic acid-b-poly(lactic acid) (HA–PLA) polymersome membrane and a model protein in the core. 

GM1 gangliosidosis (GM1) is a rare but fatal neurodegenerative disease caused by dysfunction or lack of production of lysosomal enzyme, β-galactosidase, leading to accumulation of substrates. The most promising treatments for GM1, include enzyme replacement therapy (ERT), substrate reduction therapy (SRT), stem cell therapy and gene editing. However, effectiveness is limited for neuropathic GM1 due to the restrictive nature of the blood–brain barrier (BBB). ERT and SRT alleviate substrate accumulation through exogenous supplementation over the patient’s lifetime, while gene editing could be curative, fixing the causative gene,GLB1, to enable endogenous enzyme activity. Stem cell therapy can be a combination of both, withex vivogene editing of cells to cause the production of enzymes. These approaches require special considerations for brain delivery, which has led to novel formulations. A few therapeutic interventions have progressed to early-phase clinical trials, presenting a bright outlook for improved clinical management for GM1. 

Aims: Stimuli-responsive polymersomes are promising tools for protein-based therapies, but require deeper understanding and optimization of their pathology-responsive behavior. Materials & methods: Hyaluronic acid (HA)–poly(b-lactic acid) (PLA) polymersomes self-assembled from block copolymers of varying molecular weights of HA were compared for their physical properties, degradation and intracellular behavior. Results: Major results showed increasing enzyme-responsivity associated with decreasing molecular weight. The major formulation differences were as follows: the HA(5 kDa)–PLA formulation exhibited the most pronounced release of encapsulated proteins, while the HA(7 kDa)–PLA formulation showed the most different release behavior from neutral. Conclusion: We have discovered design rules for HA–PLA polymersomes for protein delivery, with lower molecular weight leading to higher encapsulation efficiency, greater release and greater intracellular uptake.