Bioinspired polydopamine interfacial engineering of plant-derived exosomes enhances doxorubicin bioactivity in 2D and 3D breast cancer models.

Plant-derived exosomes have emerged as promising bioinspired nanomaterials for drug delivery; however, limited control over their surface interactions and therapeutic behavior restricts their functional potential. Herein, we introduce a bioinspired interfacial engineering strategy that simultaneously integrates polydopamine (PDA) surface engineering and doxorubicin loading through a one-step ultrasonic assembly process. This approach enables tunable regulation of exosome surface chemistry, colloidal stability, and drug retention without compromising nanoscale architecture. The engineered exosomes exhibit a uniform size of 179.2 nm (PDI = 0.303) and high encapsulation efficiency (85.8%), while demonstrating suppressed premature drug leakage under physiological conditions (19% cumulative release at pH 7.4 over 7 days) and accelerated release in acidic environments. More importantly, PDA-mediated surface modulation significantly alters exosome-cell interactions, resulting in enhanced cellular internalization and amplified apoptosis in MCF-7 and MDA-MB-231 breast cancer cells. In physiologically relevant 3D tumor models based on electrospun polycaprolactone/chitosan hydrogel droplet scaffolds, PDA-engineered exosomes reduce the IC₅₀ of doxorubicin to 36.7 μM compared with 88.3 μM for free drug, while maintaining reduced cytotoxicity toward normal fibroblasts. These results demonstrate that polydopamine-based interfacial engineering improves the stability, release behavior, and therapeutic bioactivity of plant-derived exosome nanocarriers, supporting their potential application in advanced in vitro cancer treatment models.