Zwitterionic Peptide Cloak Mimics Protein Surfaces for Protein Protection.

Inspired by the amino acid composition of natural protein surfaces, we developed a zwitterionic cloak containing multi-layers of short alternating glutamic acid and lysine (EK) peptides as a facile, highly effective and low-immunogenicity approach for the protection and delivery of biotherapeutics. Each EK layer grafted to proteins provides multiple times of new lysine reaction sites for the growth of subsequent EK layers. This unique design allows EK peptides to achieve high coating density on proteins, overcoming the limitation of traditional conjugation strategies that rely on the number of innate lysine groups. A triple-layer EK cloak manifests to successfully eliminate the specific and non-specific interactions of protected asparaginase with biological media while prolong the drug circulation time and significantly mitigate its immunogenicity in vivo, suggesting an EK peptide cloak as a promising approach to improve the safety and efficacy of biotherapeutics.

Recent Advances in Lipid Nanoparticles and Their Safety Concerns for mRNA Delivery.

INTRODUCTION: The advent of lipid nanoparticles (LNPs) as a delivery platform for mRNA therapeutics has revolutionized the biomedical field, particularly in treating infectious diseases, cancer, genetic disorders, and metabolic diseases. Recent Advances in Therapeutic LNPs: LNPs, composed of ionizable lipids, phospholipids, cholesterol, and polyethylene glycol (PEG) lipids, facilitate efficient cellular uptake and cytosolic release of mRNA while mitigating degradation by nucleases. However, as synthetic entities, LNPs face challenges that alter their therapeutic efficacy and safety concerns. Toxicity/Reactogenicity/Immunogenicity: This review provides a comprehensive overview of the latest advancements in LNP research, focusing on preclinical safety assessments encompassing toxicity, reactogenicity, and immunogenicity. Summary and Outlook: Additionally, it outlines potential strategies for addressing these challenges and offers insights into future research directions for enhancing the application of LNPs in mRNA therapeutics.

Hidden hydrophobicity impacts polymer immunogenicity.

Antibodies against poly(ethylene glycol) (PEG) have been found to be the culprit of side reactions and efficacy loss of a number of PEGylated drugs. Fundamental mechanisms of PEG immunogenicity and design principles for PEG alternatives still have not been fully explored. By using hydrophobic interaction chromatography (HIC) under varied salt conditions, we reveal the "hidden" hydrophobicity of those polymers which are generally considered as hydrophilic. A correlation between the hidden hydrophobicity of a polymer and its polymer immunogenicity is observed when this polymer is conjugated with an immunogenic protein. Such a correlation of hidden hydrophobicity vs. immunogenicity for a polymer also applies to corresponding polymer-protein conjugates. Atomistic molecular dynamics (MD) simulation results show a similar trend. Based on polyzwitterion modification and with this HIC technique, we are able to produce extremely low-immunogenic protein conjugates as their hydrophilicity is pushed to the limit and their hydrophobicity is eliminated, breaking the current barriers of eliminating anti-drug and anti-polymer antibodies.

High-Strength and Nonfouling Zwitterionic Triple-Network Hydrogel in Saline Environments.

Zwitterionic hydrogels have received great attention due to their excellent nonfouling and biocompatible properties, but they suffer from weak mechanical strength in the saline environments important for biomedical and engineering applications due to the "anti-polyelectrolyte" effect. Conventional strategies to introduce hydrophobic or non-zwitterionic components to increase mechanical strength compromise their nonfouling properties. Here, a highly effective strategy is reported to achieve both high mechanical strength and excellent nonfouling properties by constructing a pure zwitterionic triple-network (ZTN) hydrogel. The strong electrostatic interaction and network entanglement within the triple-network structure can effectively dissipate energy to toughen the hydrogel and achieve high strength, toughness, and stiffness in saline environments (compressive fracture stress 18.2 ± 1.4 MPa, toughness 1.62 ± 0.03 MJ m-3 , and modulus 0.66 ± 0.03 MPa in seawater environments). Moreover, the ZTN hydrogel is shown to strongly resist the attachment of proteins, bacteria, and cells. The results provide a fundamental understanding to guide the design of tough nonfouling zwitterionic hydrogels for a broad range of applications.

High-strength and fibrous capsule-resistant zwitterionic elastomers.

The high mechanical strength and long-term resistance to the fibrous capsule formation are two major challenges for implantable materials. Unfortunately, these two distinct properties do not come together and instead compromise each other. Here, we report a unique class of materials by integrating two weak zwitterionic hydrogels into an elastomer-like high-strength pure zwitterionic hydrogel via a "swelling" and "locking" mechanism. These zwitterionic-elastomeric-networked (ZEN) hydrogels are further shown to efficaciously resist the fibrous capsule formation upon implantation in mice for up to 1 year. Such materials with both high mechanical properties and long-term fibrous capsule resistance have never been achieved before. This work not only demonstrates a class of durable and fibrous capsule-resistant materials but also provides design principles for zwitterionic elastomeric hydrogels.