Ruairí P. Brannigan

This review explores the recent advancements in polymer-assisted delivery systems for antisense oligonucleotides (ASOs) and their potential in precision disease treatment. Synthetic polymers have shown significant promise in enhancing the delivery, stability, and therapeutic efficacy of ASOs by addressing key challenges such as cellular uptake, endosomal escape, and reducing cytotoxicity. The review highlights key studies from the past decade demonstrating how these polymers improve gene silencing efficiencies, particularly in cancer and neurodegenerative disease models. Despite the progress achieved, barriers such as immunogenicity, delivery limitations, and scalability still need to be overcome for broader clinical application. Emerging strategies, including stimuli-responsive polymers and advanced nanoparticle systems, offer potential solutions to these challenges. The review underscores the transformative potential of polymer-enhanced ASO delivery in personalised medicine, emphasising the importance of continued innovation to optimise ASO-based therapeutics for more precise and effective disease treatments.

The success of thermoplastic elastomers is owed to the wide range of thermal, mechanical and degradation properties that enable them to be tuned to myriad applications. In large, this is achieved through the manipulation of the chemical structure of their component parts e.g. polyol, diisocyanate and diol chain extender. The permutation of diol extenders is of great interest industrially owing to their commercial availability and ease of synthesis and purification, however, the incorporation of extenders with post-polymerisation modifiable sites, specifically moieties prone to ‘click’ coupling chemistries has been relatively overlooked until recent times. Herein, the application of ‘acetal-diols’, (2-phenyl-1,3-dioxane-5,5-diyl)dimethanol (C_Ph) and (2-(norbornene)-1,3-dioxane-5,5-diyl)dimethanol (C_Nb), as extenders in the synthesis of novel thermoplastic polyurethanes (TPUs) is described. The assessment of their structure–property relationship reveals that the material properties are highly tailorable based on their urethane content. Furthermore, norbornene ‘click’ chemistries could be utilised post-polymerisation as a method of manipulating the materials’ hydrophilicity and degradability.

Mucoadhesion is defined as the adherence of a synthetic or natural polymer to a mucosal membrane via physical or chemical interactions. Mucoadhesive materials are widely used to develop dosage forms for transmucosal drug delivery via ocular, nasal, esophageal, oral, vaginal, rectal, and intravesical routes of administration. This review will discuss some of the most prominent and recent synthetic methodologies employed to modify polymeric materials in order to enhance their mucoadhesive properties. This includes chemical conjugation of polymers with molecules bearing thiol‐, catechol‐, boronate‐, acrylate‐, methacrylate‐, maleimide‐, and N‐hydroxy(sulfo)succinimide ester‐ groups.

Owing to their wide range of inherent functionality, hydrolytic stability, biodegradability, and low toxicity, polypeptide‐based materials have been increasingly exploited for controlled drug release applications. More recently, the incorporation of poly(α‐peptoid)s such as poly(sarcosine) into polypeptide‐based materials has been investigated owing to their potential as naturally derived “stealth polymers.” Here the synthesis of novel amphiphilic polypept(o)ide nanoparticles is described utilizing silica templates as a macroinitiator for the ring‐opening copolymerization of l‐tryptophan and d/l‐phenylalanine NCAs and subsequent chain extension with sarcosine NCA. These particles are subsequently crosslinked utilizing the TAD‐indole “click” chemistry and the silica templates are eroded via treatment with HF yielding core crosslinked amphiphilic polypept(o)ide nanostructures. This synthetic strategy offers a unique platform to yield naturally‐derived degradable core‐crosslinked nanostructures, which may have the potential to be utilized in the future as delivery vehicles for hydrophobic small molecules.

Polymeric nanoparticles are widely investigated to enhance the selectivity of therapeutics to targeted sites, as well as to increase circulation lifetime and water solubility of poorly soluble drugs. In contrast to the encapsulation of the cargo into the nanostructures, which traditionally requires the use of complex synthetic approaches or time-consuming self-assembly methods, the conjugation directly to the polymer backbone allows better control on the loading and selective triggered release. In this work we report a simple procedure to create biodegradable polycarbonate graft copolymer nanoparticles via a ring opening polymerization and subsequent post-polymerization modification strategies. The polymer, designed with both pH responsive acetal linkages and a norbornene group, allows for highly efficient post-polymerization modifications through a range of chemistries to conjugate imaging agents and solubilizing arms to direct self-assembly. To demonstrate the potential of this approach, polycarbonate-based nanoparticles were tested for biocompatibility and ability to be internalized in A549 and IMR-90 cell lines.

Polyester-based polymers represent excellent candidates in synthetic biodegradable and bioabsorbable materials for medical applications owing to their tailorable properties. The use of synthetic polyesters as biomaterials offers a unique control of morphology, mechanical properties and degradation profile through monomer selection, polymer composition (i.e. copolymer vs. homopolymer, stereocomplexation etc.) and molecular weight. Within this review, the synthetic routes, degradation modes and application of aliphatic polyester- and polycarbonate-based biomaterials are discussed.

Novel maleimide-functionalised nanogels have been synthesised via the polymerisation of 2,5-dimethylfuran-protected 3-maleimidoethyl butylacrylate in the presence of presynthesised poly(N-vinylpyrrolidone) (PVP) nanogel scaffolds using surfactant-free emulsion polymerisation techniques. The protected maleimide nanogels were subsequently deprotected to generate the reactive maleimide group via a retro-Diels–Alder reaction. These activated nanogels were found to exhibit excellent mucoadhesive properties on ex vivo conjunctival tissue when compared to the known mucoadhesive chitosan. In order to determine the viability of the materials as drug carriers, nanogels were loaded with a model drug compound and the in vitro release kinetics were analysed. The nanogels could sustain the release of a model drug compound over several hours owing to the swellable hydrophilic nanogel structure, exhibiting first order release kinetics. As a consequence, these findings support the potential of these maleimide-bearing nanogels as a novel platform for sustained drug delivery.