Indocyanine Green Aggregation-Induced Hypotonic Stress to Remodel Aloe Exosome-like Vesicles for Enhanced Tumor Penetration and Phototherapy

As ubiquitous transport nanovesicles in cell biology, plant exosome-like vesicles (PELVs) have enormous potential to deliver drugs safely and effectively. Drug encapsulation and mechanical stability of vesicles are key limitations influencing their delivery efficiency. However, common methods (i.e., ultrasound, electroporation) for drug loading inevitably affect the inherent vesicle characteristics, which influence their stability, leakproof nature, cellular internalization, and tumor penetration. Herein, in order to balance this contradiction, we put forward a strategy to skillfully remodel aloe exosome-like vesicles (AELVs) through indocyanine green (ICG)-induced hypotonic stress during endogenous drug loading. We observe that the rigidity of AELVs is enhanced with the accumulation of long hydrocarbon chain lipids under ICG-induced hypotonic stress. Synchronously, ICG is also loaded into AELVs (ICG/AELVs, IAs), which effectively prevents secondary damage during drug loading. More interestingly, we find that hypotonic stress promotes IA secretion with less intravesicular protein, which is beneficial to enlarge their inner space for more drug loading. The IAs show great storage stability, leakproof, and antidegradation performance. Compared with control AELVs, IAs with higher rigidity are more liable to penetrate into the tumor. IAs further modifying with the AS1411 aptamer (AS1411-IAs, AIAs) exhibit high tumor targeting in vivo. After intravenous administration, the 4T1 tumor is obviously inhibited by AIAs plus NIR irradiation, which effectively improves the survival rate of tumor-bearing mice. Overall, we systematically explore the effects of drug-induced osmotic stress on PELVs during endogenous drug loading and achieve efficient tumor therapy. This work simplifies the process of drug loading in PELVs and enhances their plasticity, which provides a promising perspective for PELV-based drug delivery and clinical application.