All‐PEG‐Like Block Copolymers Self‐Assemble into Stealth Nanocarriers for Drug Delivery

ABSTRACT Poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) is a stealth polymer that does not exhibit polyethylene glycol (PEG) antigenicity. Herein, we engineered self‐assembling nanoparticles composed entirely of POEGMA by designing AB diblock copolymers with varying oligo(ethylene glycol) (EG) side chains. We found that a one‐unit difference between di‐ and tri‐ethylene glycol side chains is sufficient to induce amphiphilicity and enables temperature‐triggered self‐assembly above room temperature when the block length ratio is at least 0.25. To broaden the temperature stability window, we increased amphiphilicity by incorporating mono‐ethylene glycol into the hydrophobic block via random copolymerization, yielding nanoparticles stable between 20°C–40°C. These POEGMA nanoparticles effectively encapsulate diverse hydrophobic drugs with high loading efficiency. Notably, POEGMA‐encapsulated doxorubicin retained the drug's in vitro activity and exhibited enhanced in vivo efficacy compared to free doxorubicin due to improved pharmacokinetics. Furthermore, these nanoparticles demonstrated stealth behavior by evading recognition by anti‐PEG antibodies. This study introduces a versatile, fully POEGMA‐based platform for stealth drug delivery with tunable thermal responsiveness and high therapeutic potential.