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Treating the brain is challenging due to the restrictive blood–brain barrier, and modulus-mismatched implants often cause problems. Herein, we have fabricated copolymer hydrogels from thermoresponsive polymer, poly(N-isopropylacrylamide) (PNIPAAm), -r-hydrophilic polymer, poly(acrylic acid) (PAA), which are injectable and transform into soft implants above their lower critical solution temperature (LCST). PAA concentration can be leveraged to tune the LCST and viscosity of the PNIPAAm–r–PAA hydrogel in solution. Furthermore, the Young’s moduli of these materials, ranging from 1-4 kPa, are close to rat and human brain tissue, potentially leading to less inflammation and rejection due to significant modulus mismatch. 

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. 

GM1 gangliosidosis is a lysosomal storage disorder caused by deficiency of β-galactosidase (βgal) and subsequent accumulation of GM1 ganglioside in lysosomes. One of the pathological aspects of GM1 gangliosidosis, and other storage disorders, is impaired autophagy, i.e., a reduced fusion of autophagosomes and lysosomes to degrade cellular waste. Enzyme replacement therapy (ERT) can effectively treat systemic deficiency but is limited by immunogenicity and shortened half-life of intravenously administered enzyme. In this paper, we report a hyaluronic acid-b-polylactic acid (HA-PLA) polymersome delivery system that can achieve an enzyme-responsive and sustained delivery of βgal to promote the cell’s self-healing process of autophagy. HA-PLA polymersomes have an average diameter of 138.0 ± 17.6 nm and encapsulate βgal with an efficiency of 77.7 ± 3.4%. In the presence of model enzyme Hyaluronidase, HA-PLA polymersomes demonstrate a two-fold higher release of encapsulant than without enzyme. We also identified reduced autophagy in a cellular model of GM1 Gangliosidosis (GM1SV3) compared to healthy cells, illustrated using immunofluorescence. Enhanced autophagy was reported in GM1SV3 cells treated with βgal-loaded polymersomes. Most notably, the fusion of lysosomes and autophagosomes in GM1SV3 cells returned to normal levels of healthy cells after 24 h of polymersome treatment. The HA-PLA polymersomes described here can provide a promising delivery system to treat GM1 Gangliosidosis. 

Tweetable abstract How can we optimize the design of enzyme-responsive polymersomes to better treat disease? In this perspective, three common modes of enzymatic action in these nanoparticles are identified. 

The assassination of Julius Caesar in 44 BCE triggered a power struggle that ultimately ended the Roman Republic and, eventually, the Ptolemaic Kingdom, leading to the rise of the Roman Empire. Climate proxies and written documents indicate that this struggle occurred during a period of unusually inclement weather, famine, and disease in the Mediterranean region; historians have previously speculated that a large volcanic eruption of unknown origin was the most likely cause. Here we show using well-dated volcanic fallout records in six Arctic ice cores that one of the largest volcanic eruptions of the past 2,500 y occurred in early 43 BCE, with distinct geochemistry of tephra deposited during the event identifying the Okmok volcano in Alaska as the source. Climate proxy records show that 43 and 42 BCE were among the coldest years of recent millennia in the Northern Hemisphere at the start of one of the coldest decades. Earth system modeling suggests that radiative forcing from this massive, high-latitude eruption led to pronounced changes in hydroclimate, including seasonal temperatures in specific Mediterranean regions as much as 7 °C below normal during the 2 y period following the eruption and unusually wet conditions. While it is difficult to establish direct causal linkages to thinly documented historical events, the wet and very cold conditions from this massive eruption on the opposite side of Earth probably resulted in crop failures, famine, and disease, exacerbating social unrest and contributing to political realignments throughout the Mediterranean region at this critical juncture of Western civilization.