DeJulius, C. | Search bioRxiv

bioRxiv2026

IOP-independent treatment for neurodegeneration in glaucoma using optimized ROS-scavenging microparticles for sustained release of erythropoietin

Glaucoma is a slow-progressing neurodegenerative disease of the optic projection to the brain and a leading cause of blindness worldwide. Current treatments are targeted towards lowering intraocular pressure (IOP), the only known, modifiable risk factor; however, this strategy is ineffective in many patients. An early hallmark of glaucomatous neurodegeneration is increased reactive oxygen species (ROS), representing an alternative opportunity for intervention to halt or slow disease progression. In this work, we optimize a ROS-scavenging copolymer, poly(propylene sulfide-co-ethylene sulfide) (PPSES), for formulation of size-controlled, stabilized, antioxidant microparticles (MPs) for sustained release of the protein erythropoietin (EPO). EPO promotes biological antioxidant defense via activation of NRF2-mediated transcription of antioxidant genes. This MP system overcomes the short half-life of EPO and leverages the combined benefits of bioactive EPO with long-lasting, inherently antioxidant PPSES MPs. The lead EPO-MP formulation preserves neurons in both mouse and non-human primate models of glaucoma through suppression of oxidative stress and optic nerve degeneration. EPO-loaded PPSES MPs represent a translationally relevant therapy for long-term management of glaucoma independent of IOP.

bioengineering↗

bioRxiv2023

Structural Optimization of siRNA Conjugates for Albumin Binding Achieves Effective MCL1-Targeted Cancer Therapy

The high potential for therapeutic application of siRNAs to silence traditionally undruggable oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, siRNAs were optimized for in situ binding to albumin through C18 lipid modifications to improve pharmacokinetics and tumor delivery. Systematic variation of siRNA conjugates revealed a lead structure with divalent C18 lipids each linked through three repeats of hexaethylene glycol connected by phosphorothioate bonds. Importantly, we discovered that locating the branch site of the divalent lipid structure proximally (adjacent to the RNA) rather than at a more distal site (after the linker segment) promotes association with albumin, while minimizing self-assembly and lipoprotein association. Comparison to higher albumin affinity (diacid) lipid variants and siRNA directly conjugated to albumin underscored the importance of conjugate hydrophobicity and reversibility of albumin binding for siRNA delivery and bioactivity in tumors. The lead conjugate increased tumor siRNA accumulation 12-fold in orthotopic mouse models of triple negative breast cancer over the parent siRNA. When applied for silencing of the anti-apoptotic oncogene MCL-1, this structure achieved approximately 80% MCL1 silencing in orthotopic breast tumors. Furthermore, application of the lead conjugate structure to target MCL1 yielded better survival outcomes in three independent, orthotopic, triple negative breast cancer models than an MCL1 small molecule inhibitor. These studies provide new structure-function insights on optimally leveraging siRNA-lipid conjugate structures that associate in situ with plasma albumin for molecular-targeted cancer therapy.

bioengineering↗