Exploring release mechanisms by disrupting π–π stacking regions in stable micelles†

π–π stacking strategies can enhance the stability performance of delivery platforms but are often restricted by incomplete drug release performance, even with the help of crosslinking strategies. Therefore, there has been considerable interest in enhancing the drug release performance by disrupting the π–π stacking region (structural rearrangements). Herein, we synthesized poly(3-(isobutyloxy)-2-oxopropyl benzoate)-b-poly(2-hydroxybutyl methacrylate)-co-poly((ethylene glycol)methylether methacrylate) [PBOOPMA-b-P(HBMA-co-PEGMA), PHB] and revealed the drug release mechanism of PHB-based micelles. The structural rearrangements derived from the crosslinking strategy were revealed to improve the early release performance by 43–55% using micellar dissolutions. Moreover, the esterase-responsive strategy was elucidated to induce reassembly with 77–79% size variation, intensifying the structural rearrangements, which was also synergistic with the crosslinking strategy. Based on the advantages of improving drug release performance, the esterase-responsive strategy was considered a promising candidate for enhancing late release performance. Meanwhile, it is believed that such responsive modulation (crosslinking, esterase-responsive) in the π–π stacking region will become highly promising for subsequent research. Finally, the biosafety of 95.81% at 400 mg L⁻¹ and drug cytotoxicity of IC₅₀ ≈ 2.5 mg L⁻¹ of PHB-EDE@CPT were also validated, confirming the broad application prospects of PHB-based crosslinked micelles.