Proteins and their interactions in and out of cells must be well-orchestrated for the healthy functioning and regulation of the body. Even the slightest disharmony can cause diseases. Therapeutic peptides are short amino acid sequences (generally considered <50 amino acids) that can naturally mimic the binding interfaces between proteins and thus, influence protein–protein interactions. Because of their fidelity of binding, peptides are a promising next generation of personalized medicines to reinstate biological harmony. Peptides as a group are highly selective, relatively safe, and biocompatible. However, they are also vulnerable to many in vivo pharmacologic barriers limiting their clinical translation. Current advances in molecular, chemical, and nanoparticle engineering are helping to overcome these previously insurmountable obstacles and improve the future of peptides as active and highly selective therapeutics. In this review, we focus on self-assembled vehicles as nanoparticles to carry and protect therapeutic peptides through this journey, and deliver them to the desired tissue.

Wet-dry cycling on the early Earth is thought to have facilitated production of molecular building blocks of life, but its impact on self-assembly and compartmentalization remains largely unexplored. Here, we investigate dehydration/rehydration of complex coacervates, which are membraneless compartments formed by phase separation of polyelectrolyte solutions. Solution compositions are identified for which tenfold water loss results in maintenance, disappearance, or appearance of coacervate droplets. Systems maintaining coacervates throughout the dehydration process are further evaluated to understand how their compartmentalization properties change with drying. Although added total RNA concentrations increase tenfold, RNA concentration within coacervates remains steady. Exterior RNA concentrations rise, and exchange rates for encapsulated versus free RNAs increase with dehydration. We explain these results in light of the phase diagram, with dehydration-driven ionic strength increase being particularly important in determining coacervate properties. This work shows that wet-dry cycling can alter the phase behavior and protocell-relevant functions of complex coacervates.

Modifications to the aqueous solution self-assembly and thermoresponsive properties of poly(N-isopropylacrylamide) (PNIPAm) can be achieved by hydrophobic end-group functionalization and incorporation of hydrophilic N,N-dimethylacrylamide (DMA) repeat units. Although these variations have been studied separately in the past, the simultaneous effects of both modifications have not been investigated systematically. Herein, we report the synthesis of six NIPAM and DMA based statistical, ABA triblock, and ABABA pentablock copolymers using reversible addition–fragmentation chain transfer (RAFT) polymerization, each containing one or two dodecyl hydrocarbon end-groups. Assembly into nanoscale particles and thermoresponsive properties in phosphate buffered saline were studied using light scattering and diffusion ordered NMR spectroscopy. Cloud points (T_cp) remained between 30–45 °C, notwithstanding hydrophobic modification. Copolymers with two alkyl tails assembled into flower-like micelles below the T_cp. The monofunctional statistical copolymer formed a core–shell assembly and the monofunctional ABA and ABABA polymers were molecularly dissolved. Above the T_cp, reversible precipitation was observed in all systems except for the monofunctional ABABA pentablock, which unexpectedly formed uniform large (>100 nm diameter) aggregates interpreted as mesoglobules. These results demonstrate surprising and delicately balanced tradeoffs between short non-polar end groups and tailored hydrophobicity in the nanoscale self-assembly of PNIPAm based copolymers in water near the lower critical solution temperature.