Green surfactants reveal mechanistic principles governing polymeric microbubble formation and function.

Poly(butyl cyanoacrylate) microbubbles (PBCA MB) are clinically investigated ultrasound-responsive materials whose formation is governed by surfactant-mediated interfacial templating. Here, we used a chemically diverse panel of 14 commercially designated greener non-ionic surfactants to clarify how surfactant chemistry governs PBCA MB formation and performance. By combining physicochemical analysis, dissipative particle dynamics simulations, microscopy, drug-loading experiments, and acoustic characterization, we determined how the architecture of the hydrophobic moiety, PEG chain length, and hydrophilic-lipophilic balance shape MB yield, shell composition, morphology, and function. The hydrophobic tail structure primarily influenced MB yield, while increasing PEG chain length shifted the morphology toward asymmetric particles. Surfactant incorporation into PBCA MB shells depended on surfactant hydrophilic-lipophilic balance, and dissipative particle dynamics simulations indicated preferential surfactant enrichment at the polymer-water interface. Brij O20 and Ecosurf SA-9 increased drug loading by 6.2- and 4.8-fold relative to conventional Triton X-100-generated MB, while acoustic performance could be tuned toward either greater stability or stronger non-linear, disruption-prone behavior. Together, these findings clarify the role of surfactant chemistry in PBCA MB synthesis and promote surfactant design as a practical route to tailor MB morphology, shell composition, drug loading, and acoustic performance.