Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy.

The high potential of siRNAs to silence oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, divalent lipid-conjugated siRNAs are optimized for in situ binding to albumin to improve pharmacokinetics and tumor delivery. Systematic variation of the siRNA conjugate structure reveals that the location of the linker branching site dictates tendency toward albumin association versus self-assembly, while the lipid hydrophobicity and reversibility of albumin binding also contribute to siRNA intracellular delivery.

Hybrid Shear-thinning Hydrogel Integrating Hyaluronic Acid with ROS-Responsive Nanoparticles.

Nanoparticle (NP) supra-assembly offers unique opportunities to tune macroscopic hydrogels' mechanical strength, material degradation, and drug delivery properties. Here, synthetic, reactive oxygen species (ROS)-responsive NPs are physically crosslinked with hyaluronic acid (HA) through guest-host chemistry to create shear-thinning NP/HA hydrogels. A library of triblock copolymers composed of poly(propylene sulfide)--poly(N,N-dimethylacrylamide)--poly(N,N-dimethylacrylamide--N-(1-adamantyl)acrylamide) are synthesized with varied triblock architectures and adamantane grafting densities and then self-assembled into NPs displaying adamantane on their corona.

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 binding to albumin through C lipid modifications to improve pharmacokinetics and tumor delivery. Systematic variation of siRNA conjugates revealed a lead structure with divalent C lipids each linked through three repeats of hexaethylene glycol connected by phosphorothioate bonds.

Reactive oxygen species-degradable polythioketal urethane foam dressings to promote porcine skin wound repair.

Porous, resorbable biomaterials can serve as temporary scaffolds that support cell infiltration, tissue formation, and remodeling of nonhealing skin wounds. Synthetic biomaterials are less expensive to manufacture than biologic dressings and can achieve a broader range of physiochemical properties, but opportunities remain to tailor these materials for ideal host immune and regenerative responses. Polyesters are a well-established class of synthetic biomaterials; however, acidic degradation products released by their hydrolysis can cause poorly controlled autocatalytic degradation.

Profiles of abuse and neglect and the association with mental health indicators among a large sample of boys and girls from India.

Background: Child abuse and neglect (CAN) is a major public health concern, but limited data are available on the occurrence, co-occurrence, and correlates of these phenomena outside Western societies.

Objectives: The first aim of this study was to establish the prevalence of CAN across two settings (inside and outside the home) among children and adolescents in Mumbai, India. Another aim was to use latent class analysis (LCA) to identify meaningful profiles of maltreatment, and to examine how class membership is associated with mental wellbeing.

Kupffer cell release of platelet activating factor drives dose limiting toxicities of nucleic acid nanocarriers.

This work establishes that Kupffer cell release of platelet activating factor (PAF), a lipidic molecule with pro-inflammatory and vasoactive signaling properties, dictates dose-limiting siRNA nanocarrier-associated toxicities. High-dose intravenous injection of siRNA-polymer nano-polyplexes (si-NPs) elicited acute, shock-like symptoms in mice, associated with increased plasma PAF and consequently reduced PAF acetylhydrolase (PAF-AH) activity. These symptoms were completely prevented by prophylactic PAF receptor inhibition or Kupffer cell depletion.

Enhanced stem cell retention and antioxidative protection with injectable, ROS-degradable PEG hydrogels.

Poly(ethylene glycol) (PEG) hydrogels crosslinked with enzyme-cleavable peptides are promising biodegradable vehicles for therapeutic cell delivery. However, peptide synthesis at the level required for bulk biomaterial manufacturing is costly, and fabrication of hydrogels from scalable, low-cost synthetic precursors while supporting cell-specific degradation remains a challenge. Reactive oxygen species (ROS) are cell-generated signaling molecules that can also be used as a trigger to mediate specific in vivo degradation of biomaterials.

Porcine Ischemic Wound-Healing Model for Preclinical Testing of Degradable Biomaterials.

Impaired wound healing that mimics chronic human skin pathologies is difficult to achieve in current animal models, hindering testing and development of new therapeutic biomaterials that promote wound healing. In this article, we describe a refinement and simplification of the porcine ischemic wound model that increases the size and number of experimental sites per animal. By comparing three flap geometries, we adopted a superior configuration (15 × 10 cm) that enabled testing of twenty 1 cm wounds in each animal: 8 total ischemic wounds within 4 bipedicle flaps and 12 nonischemic wounds.