Polyphosphoester-Based Bottlebrush Block Copolymers as Fully Degradable Stable Micellar Carriers

Poly(ethylene glycol) (PEG)-containing block copolymer micelles have been widely used as model systems for drug delivery. However, the non-biodegradability and potential immunogenicity of PEG have driven the search for biodegradable alternatives. Here, a biodegradable, hydrophilic polyphosphoester was employed to construct amphiphilic bottlebrush block copolymers for PEG-free polymeric micelles. Using norbornene-functionalized poly(ethyl ethylene phosphate) (NB-PEEP) and poly(lactic acid) (NB-PLA) macromonomers, a well-defined bottlebrush block copolymer, PNB-g-(PEEP-b-PLA), was synthesized via ring-opening metathesis polymerization (ROMP). Spherical micelles were formed in aqueous solution with average diameters of 59.2 ± 24.3 nm and 44.1 ± 3.9 nm, as confirmed by dynamic light scattering (DLS) and scanning electron microscopy (SEM), respectively. The critical micelle concentration (CMC) was approximately 1 × 10⁻³ mg mL⁻¹, which is about two orders of magnitude lower than that of typical small-molecule surfactants, indicating stable micelle formation at low polymer concentrations. Loading studies using Nile Red as a model payload demonstrated that the bottlebrush copolymer exhibited improved loading performance compared with the corresponding linear PEEP-b-PLA analogue under identical loading conditions. Owing to the bottlebrush architecture, degradation of both the PEEP and PLA side chains induces release of the payload. These results highlight the role of macromolecular architecture in controlling micellar assembly and loading performance, establishing PNB-g-(PEEP-b-PLA) as a fully biodegradable polymeric carrier.