Two Principles for Polymersomes with Ultrahigh Biomacromolecular Loading Efficiencies: Acid-Induced Adsorption and Affinity-Enhanced Attraction

Herein, two novel principles are proposed for the judicious design of polymersomes with ultrahigh loading efficiencies for various biomacromolecules: (1) acid-induced adsorption (AIA) for proteins and (2) affinity-enhanced attraction (AEA) for nucleic acids. The former principle (AIA) is assisted by the triazole group within the polymersome membrane. The latter principle (AEA) is based on intermolecular interactions, such as the anion−π interaction and π–π stacking, which can be achieved by the judicious design of polymersomes with structurally similar repeat units as the biomacromolecular cargo [plasmid deoxyribonucleic acid (DNA) and ribonucleic acid (RNA)]. According to these two principles, a poly(ethylene oxide)45-b-poly((α-(cinnamoyloxymethyl)-1,2,3-triazol)caprolactone)90 (PEO45-b-PCTCL90) block copolymer was prepared and self-assembled into polymersomes by directly dispersing the polymer in water. This approach allowed simultaneous polymer self-assembly and ultrahigh biomacromolecular loading efficiencies for hemoglobin (79%), plasmid DNA (75%), and RNA (85%). The AIA and AEA principles, responsible for these high loading efficiencies, were confirmed by transmission electron microscopy and molecular dynamics computer simulations. Moreover, this novel polymersome has a biodegradable membrane with photocross-linkable groups; this solves a long-standing problem in balancing electrosteric stability and biodegradability. Finally, we demonstrated the biomedical potential of the PEO45-b-PCTCL90 polymersome. Polymersomes loaded with green fluorescent protein-encoded plasmid of different sizes were efficiently transfected into HepG2 cells without interfering the gene expression. Overall, we propose two principles for designing protein and nucleic acid vectors with ultrahigh loading capability and shed light on developing noncationic vectors with tunable biodegradability.