Acoustically active poly(tBMA) floral nanocages for ultrasound-guided spatiotemporal cargo release

Clinically approved ultrasound contrast agents, including microbubbles and nanobubbles, suffer from limited circulation stability, restricted extravasation, and dependence on exogenous gas cores, necessitating structurally inherent cavitation-active nanocarriers. Herein, we report acoustically active mesoporous polymeric nanoparticles (MNPs), also hereby referred to as 'Floral nanocages' synthesized via diffusion-guided seeded emulsion polymerization of tert-butyl methacrylate (tBMA) within polystyrene (PS) templates, where confined polymerization-induced phase separation generated floral-like mesoporous architectures with intrinsically entrapped air pockets serving as endogenous cavitation nuclei. Field emission scanning electron microscopy (FESEM), high-resolution transmission electron microscopy (HRTEM), and small-angle X-ray scattering (SAXS) analyses confirmed radially aligned disordered mesoporous frameworks with characteristic structural correlation lengths of ∼45-60 nm, while thermogravimetric analysis (TGA), derivative thermogravimetry (DTG), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), and ζ-potential measurements verified successful poly(tertbutyl methacrylate)/divinyl benzene (PtBMA/DVB) network formation and nanoconfinement-induced structural stabilization. Under 1 MHz ultrasound irradiation, the MNPs exhibited intensity-dependent cargo release, showing a ∼3-fold enhancement in cumulative release at 8 W cm^-2 relative to passive diffusion, with near-complete release achieved within 4-5 min, whereas 4 W cm^-2 produced a sustained release profile (t_1/2 ≈ 1.5 min; complete release ≈6 min). Release kinetics followed the Korsmeyer-Peppas model, indicating anomalous non-Fickian transport governed by matrix relaxation and ultrasound-enhanced diffusion. In tissue-mimicking agarose phantoms containing millifluidic channels, ultrasound activation produced a ∼1.7-fold increase in mean fluorescence intensity and a ∼71-fold expansion in the activated release area compared with non-exposed controls. These structurally inherent cavitation-active nanocages provide a versatile platform for ultrasound-triggered spatiotemporal cargo delivery without exogenous contrast agents. Key challenges for future translation include improving the long-term colloidal stability under physiological serum conditions and overcoming the polymer matrix's inherent hydrophobicity to enhance systemic circulation and shelf life. These limitations may be effectively addressed through PEGylation and other surface-engineering strategies. Further integration with targeting ligands and biologically active cargoes may further expand applications in cancer therapy, blood-brain barrier (BBB) modulation, and nonviral gene delivery.