Potential of novel nanomedicine combining bioactivation and PROTAC technology for lung cancer treatment

Lung cancer is one of the most prevalent and deadly malignancy worldwide. Non-small cell lung cancer (NSCLC) accounts for about 85%–90% of cases, and its heterogeneity and drug resistance pose serious treatment challenges. Recently, a study on NSCLC has reported a pH-responsive magnetic nanoparticle system, offering a new approach to improve therapeutic outcomes.

The significance of this research lies in its dual approach to tackling two major challenges in lung cancer treatment: the poor targeting precision of conventional drugs leading to off-target toxicity, and cancer cells' tendency to develop resistance to single-agent therapies. This nanoplatform is specifically designed to face both issues simultaneously.

A collaborative team led by Li Xinchun from Guangzhou Medical University Affiliated First Hospital and Yuan Youyong from South China University of Technology's School of Biomedical Science and Engineering has developed a pH-responsive magnetic nanoplatform for treating NSCLC. The core innovation of this research lies in the creation of a "synergistic therapy system." This system co-encapsulates two therapeutic agents—the NQO1-dependent drug β-lapachone (β-lap) and a PARP1-targeting proteolysis-targeting chimeras (PROTAC)—within nanoparticles, which are coated with a pH-responsive metal-phenolic network shell. This design enables drug release triggered by the acidic tumor microenvironment.

By leveraging the therapeutic window created by the concurrent overexpression of both NQO1 and PARP1 in NSCLC, the system achieves two critical functions: it allows real-time monitoring of drug distribution via magnetic resonance imaging (MRI), while simultaneously delivering a "dual-strike" effect within tumor cells. Specifically, NQO1-dependent activation of β-lap generates reactive oxygen species (ROS) that induce DNA damage. Concurrently, PROTAC-mediated degradation of PARP1 not only preserves the cofactors essential for ROS production but, more importantly, disrupts the DNA repair machinery.

The research team emphasized that the current findings represent preliminary work. This study offers a new direction for NSCLC treatment and demonstrates the potential of combining bioactivated therapy with protein degradation technology.

This work was supported by the Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University of China (2023A03J0355), OpenProject of State Key Laboratory of Respiratory Disease of China (SKIRD OP-202311) and Guangdong Provincial Zhong Nanshan Medical Foundation of China (ZNS-XS-ZZ-202409-007).

About Nano Research

Nano Research is a peer-reviewed, open access, international and interdisciplinary research journal, sponsored by Tsinghua University and the Chinese Chemical Society, published by Tsinghua University Press on the platform SciOpen. It publishes original high-quality research and significant review articles on all aspects of nanoscience and nanotechnology, ranging from basic aspects of the science of nanoscale materials to practical applications of such materials. After 18 years of development, it has become one of the most influential academic journals in the nano field. Nano Research has published more than 1,000 papers every year from 2022, with its cumulative count surpassing 7,000 articles. In 2024 InCites Journal Citation Reports, its 2024 IF is 9.0 (8.7, 5 years), and it continues to be the Q1 area among the four subject classifications. Nano Research Award, established by Nano Research together with TUP and Springer Nature in 2013, and Nano Research Young Innovators (NR45) Awards, established by Nano Research in 2018, have become international academic awards with global influence.