Mingzhou Jiang,1,* Yiming Wang,2,* Jinjin Zhang,2,* Xi Fan,1 Milayi Jieensi,1 Fang Ding,2 Yiqing Wang,1 Xiaotian Sun1 

1Department of Cardiothoracic Surgery, Huashan Hospital of Fudan University, Shanghai, People’s Republic of China; 2Department of Cardiology, Huashan Hospital of Fudan University, Shanghai, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yiqing Wang; Xiaotian Sun, Department of Cardiothoracic Surgery, Huashan Hospital of Fudan University, 12 Wulumuqi Road, Shanghai, 200040, People’s Republic of China, Email wangyiqing@huashan.org.cn; drsunxiaotian@126.com

Background: Biocompatible nanocarriers are widely employed as drug-delivery vehicles for treatment. Nevertheless, indiscriminate drug release, insufficient organ-specific targeting, and systemic toxicity hamper nanocarrier effectiveness. Stimuli-responsive nano-sized drug delivery systems (DDS) are an important strategy for enhancing drug delivery efficiency and reducing unexpected drug release.
Methods: This study introduces a temperature- and ultrasound-responsive nano-DDS in which the copolymer p-(MEO2MA-co-THPMA) is grafted onto mesoporous iron oxide nanoparticles (MIONs) to construct an MPL-p nano-DDS. The copolymer acts as a nanopore gatekeeper, assuming an open conformation at sub-physiological temperatures that allows drug encapsulation and a closed conformation at physiological temperatures that prevents unexpected drug release during circulation. Lactoferrin was conjugated to the nanoparticle surface via polyethylene glycol to gain organ-targeting ability. External ultrasonic irradiation of the nanoparticles in the targeted organs caused a conformational change of the copolymer and reopened the pores, facilitating controlled drug release.
Results: MPL-p exhibited excellent biocompatibility and rare drug release in circulation. When targeting delivery to the brain, ultrasound promoted the release of the loaded drugs in the brain without accumulation in other organs, avoiding the related adverse reactions, specifically those affecting the heart.
Conclusion: This study established a novel temperature- and ultrasound-responsive DDS that reduced systemic adverse reactions compared with traditional DDS, especially in the heart, and demonstrated excellent organ delivery efficiency.

Keywords: temperature- and ultrasound-responsive, systemic toxicity, mesoporous iron oxide nanoparticles, drug delivery