Targeting the Skin: The Study of a Bottlebrush Polymer-Antisense Oligonucleotide Conjugate in a Psoriasis Mouse Model.

The investigation of gene regulation therapeutics for the treatment of skin-related diseases is rarely explored in part due to inefficient systemic delivery. In this study, a bottlebrush polymer-antisense oligonucleotide (ASO) conjugate, termed pacDNA, designed to target IL-17 receptor A (IL-17RA), which is involved in psoriasis pathogenesis is presented. Systemic administration of pacDNA led to its accumulation in epidermis, dermis, and hypodermis of mouse skin, reduced IL-17RA gene expression in skin, and significantly reversed the development of imiquimod (IMQ)-induced psoriasis in a mouse model.

Inhalable Bottlebrush Polymer Bioconjugates as Vectors for Efficient Pulmonary Delivery of Oligonucleotides.

Antisense oligonucleotides hold therapeutic promise for various lung disorders, but their efficacy is limited by suboptimal delivery. To address this challenge, we explored the use of inhaled bottlebrush polymer-DNA conjugates, named pacDNA, as a delivery strategy. Inhaled pacDNA exhibits superior mucus penetration, achieving a uniform and sustained lung distribution in mice.

A mechanistic study on the cellular uptake, intracellular trafficking, and antisense gene regulation of bottlebrush polymer-conjugated oligonucleotides.

We have developed a non-cationic transfection vector in the form of bottlebrush polymer-antisense oligonucleotide (ASO) conjugates. Termed pacDNA (polymer-assisted compaction of DNA), these agents show improved biopharmaceutical characteristics and antisense potency while suppressing non-antisense side effects. Nonetheless, there still is a lack of the mechanistic understanding of the cellular uptake, subcellular trafficking, and gene knockdown with pacDNA.

Exploring the Structural Diversity of DNA Bottlebrush Polymers Using an Oligonucleotide Macromonomer Approach.

Herein, we demonstrate that macromonomers consisting of organics-soluble, chemically protected oligonucleotides (protDNA) and poly(ethylene glycol) (PEG) chains can be converted into bottlebrush polymers of distinct architectures via ring-opening metathesis polymerization (ROMP). Using a custom norbornene-containing phosphoramidite, two types of macromonomers were obtained: a linear norbornene-protDNA-PEG structure and a Y-shaped structure where the polymerizable norbornene group is situated at the junction where protDNA and PEG meet. With this strategy, the PEG chains can be placed either near the backbone of the bottlebrush or on its periphery, and in principle anywhere between these two extremes by adjusting the norbornene location, which makes this strategy attractive for constructing architecturally sophisticated oligonucleotide-containing copolymers.

Bottlebrush Polymer-Conjugated Melittin Exhibits Enhanced Antitumor Activity and Better Safety Profile.

Despite potency against a variety of cancers in preclinical systems, melittin (MEL), a major peptide in bee venom, exhibits non-specific toxicity, severe hemolytic activity, and poor pharmacological properties. Therefore, its advancement in the clinical translation system has been limited to early-stage trials. Herein, we report a biohybrid involving a bottlebrush-architectured poly(ethylene glycol) (PEG) and MEL.

Synthetic Approaches for Copolymers Containing Nucleic Acids and Analogues: Challenges and Opportunities.

A deep integration of nucleic acids with other classes of materials have become the basis of many useful technologies. Among these biohybrids, nucleic acid-containing copolymers has seen rapid development in both chemistry and application. This review focuses on the various synthetic approaches to access nucleic acid-polymer biohybrids spanning post-polymerization conjugation, nucleic acids in polymerization, solid-phase synthesis, and nucleoside/nucleobase-functionalized polymers.

Spherical Nucleic Acids for Topical Treatment of Hyperpigmentation.

Oligonucleotide-based materials such as spherical nucleic acid (SNA) have been reported to exhibit improved penetration through the epidermis and the dermis of the skin upon topical application. Herein, we report a self-assembled, skin-depigmenting SNA structure, which is based upon a bifunctional oligonucleotide amphiphile containing an antisense oligonucleotide and a tyrosinase inhibitor prodrug. The two components work synergistically to increase oligonucleotide cellular uptake, enhance drug solubility, and promote skin penetration.

Self-Assembled DNA-PEG Bottlebrushes Enhance Antisense Activity and Pharmacokinetics of Oligonucleotides.

Herein, we report a novel strategy to enhance the antisense activity and the pharmacokinetics of therapeutic oligonucleotides. Through the DNA hybridization chain reaction, DNA hairpins modified with poly(ethylene glycol) (PEG) form a bottlebrush architecture consisting of a double-stranded DNA backbone, PEG side chains, and antisense overhangs. The assembled structure exhibits high PEG density on the surface, which suppresses unwanted interactions between the DNA and proteins (e.

Room-Temperature Pressure Synthesis of Layered Black Phosphorus-Graphene Composite for Sodium-Ion Battery Anodes.

Sodium-ion batteries offer an attractive option for grid-level energy storage due to the high natural abundance of sodium and low material cost of sodium compounds. Phosphorus (P) is a promising anode material for sodium-ion batteries, with a theoretical capacity of 2596 mAh/g. The red phosphorus (RP) form has worse electronic conductivity and lower initial Coulombic efficiency than black phosphorus (BP), but high material cost and limited production capacity have slowed the development of BP anodes.