Poly[(R)‐3‐hydroxybutyrate] (P3HB) is a potential candidate for biomaterials due to its biocompatibility and biodegradability. However, P3HB needs to have tunable hydrophobicity, modification through chemical functionalization and the right hydrolytic stability to increase their potential for water‐based biomedical applications such as using them as in situ forming gels for drug delivery. This work focuses on using a copolymer, poly[(R)‐3‐hydroxybutyrate‐co‐4‐hydroxybutyrate] (P3HB4HB) in a thermogelling multiblock system with polypropylene glycol and polyethylene glycol to study the effect of the hydrophobic P3HB4HB on gelation properties, degradation, and drug release rates with reference to P3HB. Thermogels containing P3HB4HB segments show lower critical micellization concentration values in a range from 3 × 10−4 to 1.08 × 10−3 g mL−1 and lower critical gelation concentration values ranging from 2 to 6 wt% than that of gels containing P3HB. Furthermore, gels containing P3HB4HB degrade at a slower rate than the gels containing P3HB. Drug release studies of 5 µg mL−1 of doxorubicin show that gels containing P3HB4HB exhibit sustained release although the release rates are faster than gels containing P3HB. However, this can be modified by varying the concentration of the gels used. Process optimization of purifying the starting material is one important factor before the synthesis of these biomaterials.

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Nanoparticle−hydrogel systems have recently emerged as a class of interesting hybrid materials with immense potential for several biomedical applications. Remarkably, the incorporation of nanoparticles into a hydrogel may yield synergistic benefits lacking in a singular system. However, most synthetic strategies require laborious steps to achieve the system, severely restricting the process of translational research. Herein, a facile strategy to access a two-in-one system comprising two distinct polyurethane (PU)-based micellar systems is demonstrated and applied as a novel sustained gene delivery platform, where the two PUs are synthesized similarly but with slightly different compositions. One PU forms cationic micelles that complex with plasmid DNA (pDNA), which are loaded into a thermogel formed by another PU micellar system for the prolonged release of pDNA micelleplexes. Specifically, a thermogelling multiblock PU copolymer (denoted as EPH) was synthesized via the step-growth polymerization of poly(ethylene glycol), poly(propylene glycol), and poly(3-hydroxybutyrate). By further introducing a cationic extender, 3-(dimethylamino)-1,2propanediol, into the reaction feed, a series of cationic PUs (denoted as EPHD) with varying compositions were obtained. The EPHDs formed positively charged micelles in aqueous solutions, efficiently condensed pDNA into nano-sized micelleplexes (<200 nm) at optimized w/w ratios, and mediated transient green fluorescence protein expression in HEK293T cells at 48 h posttransfection. On the other hand, aqueous EPH solution (4 wt %) was injectable at 4 °C and rapidly gelled upon heating to 37 °C to form a stable hydrogel depot. EPHD/pDNA micelleplexes were easily loaded into EPH by mixing the solutions at 4 °C, before heating to 37 °C, leading to the resultant hydrogel system. The in vitro release study revealed that while free pDNA loaded in the thermogel was completely released in 2 weeks, the release of EPHD/pDNA micelleplexes was prolonged to at least 28 days, suggesting substantial micelleplex−hydrogel interactions. Intact, bioactive, and noncytotoxic EPHD/pDNA micelleplexes in the release media were proved by gel retardation, in vitro gene transfection, and CCK-8 cytotoxicity assay results, respectively. Collectively, this work presents a simple approach to achieving and optimizing a novel two-in-one nanoparticle−hydrogel system for the prolonged delivery of pDNA and may be promising for long-term gene delivery applications.