Lipopolymers are an essential component of liposomes and lipid nanoparticles for drug a gene delivery. Their synthesis and purification can be tedious and inefficient. Two novel and highly modular approaches for lipopolymer synthesis are discussed.[1,2] The resulting lipopolymer are utilized in the preparation of liposomes and lipid nanoparticles and their use in gene delivery and gene editing is discussed. The modular nature of the synthesis allows straightforward synthesis of a library of lipopolymers, which can be used to elucidate the biological effects of different lipopolymers in lipid nanoparticles biodistribution and transfection efficacy. In addition, results from molecular modelling of differential interaction patterns between lipopolymers and other components of lipid nanoparticles will be discussed.[3]

Polymerization-induced self-assembly (PISA) has proven to be a versatile route towards high concentrations of micellar nanostructures with tunable chemistries and morphologies. In contrast to conventional self-assembly protocols, where the synthesis and assembly of the block copolymers (BCP) are performed in two separate and consecutive steps, PISA relies on a one-pot procedure where BCP formation and assembly occur simultaneously. Typically, solvophilic polymers are chain-extended with a second, chemically distinct monomer, yielding amphiphilic BCPs. Their amphiphilic character triggers assembly into (higher-order) micellar constructs.

Recently we extended the PISA concept beyond traditional amphiphilic block copolymer systems. BCPs carrying charged segments were synthetized in the presence of oppositely charged cargo macromolecules, e.g., dendrimers or (si)RNA. In these systems, the cargo molecules act as electrostatic templates that guide the polymerization and assembly process. Given that the strength of the electrostatic interactions between the forming BCPs and cargo is tunable by ionic strength and pH, specific time-dependent reaction-assembly pathways could be designed. Preliminary results revealed that, based on a single chemical composition, regulating the assembly pathway dictates the physical-chemical characteristics of the resulting particles. We envision to leverage this pathway complexity in polyelectrolyte assembly to fundamentally understand how the structure of polymeric gene delivery vehicles impacts their in vitro performance.

The efficiency of drug nanocarriers largely depends on their interaction with biological membranes. Incorporating membrane-active agents (e.g., lipids) into drug delivery systems can enhance these interactions and improve drug efficacy.
In this study, we synthesized amphiphilic (co)polymers with lipid moieties such as cholesterol, lithocholic acid, and diacylglycerols, either in the main chain or side chains, using reversible addition-fragmentation chain transfer (RAFT) polymerization. These (co)polymers were assembled into polymeric nanoparticles, both with and without encapsulated drug molecules. Physicochemical and biological evaluations confirmed the formation of stable nanocarriers compatible with host cells, exhibiting structure-dependent cytotoxicity against selected cancer cell lines.
Acknowledgments: National Science Centre, Poland, grant no. NCN/2019/35/B/ST5/03391.

The guanidinium group is a uniquely powerful cation in gene delivery, offering strong electrostatic interactions and multivalent hydrogen bonding with DNA. Unlike primary and tertiary amines, guanidinium remains permanently charged at physiological pH, facilitating efficient complexation with nucleic acids. However, its high affinity for DNA often results in excessively stable complexes, leading to poor release and limited transfection efficiency. [1,2]

We systematically explored how guanidinium-functionalized polymers compare to amine- and phosphonium-based systems in terms of DNA complexation, release kinetics, and transfection efficiency. We further investigate how hydrophobic modifications and charge density tuning influence gene transfer performance.

Our findings reveal key insights into how guanidinium’s unique charge behaviour dictates polymer-DNA interactions and what strategies can improve its delivery potential. This talk will discuss the challenges and opportunities in harnessing guanidinium-functionalized polymers for next-generation gene delivery systems.

We are facing a shortage of new antibiotics to fight increasingly resistant bacteria. As alternative to conventional small molecule antibiotics, antimicrobial polymers (AMPs) bear great potential. These polymers contain cationic and hydrophobic groups and disrupt bacterial cell membranes through a combination of electrostatic and hydrophobic interactions. While most examples focus on ammonium-based cations, sulfonium groups are recently emerging to broaden the scope of these polymeric therapeutics. Here, main chain sulfonium polymers exhibit good antimicrobial activity. In contrast, the potential of side chain sulfonium polymers remains less explored with structure-activity relations still being limited.
To address this limitation, we thoroughly investigated key factors influencing antimicrobial activity in side-chain sulfonium-based AMPs. For this, we combined sulfonium cations with different hydrophobic (aliphatic/aromatic) and hydrophilic polyethylene glycol (PEG) groups to create a library of polymers with comparable chain lengths. For all compositions, we additionally examined the position of cationic and hydrophobic groups on the polymer backbone, i.e., we systematically compared same center and different center structures. Bactericidal tests against gram-positive and gram-negative bacteria suggest that same center polymers are more active than different center polymers. In addition, sulfonium-based AMPs show superior bactericidal activity and selectivity when compared to their quaternary ammonium cationic analogues.
Ultimately, we found that PEG-containing block copolymers show synergistic antimicrobial activity in combination with conventional small molecule antibiotics.