Bioengineering virus-like particles derived from human bocavirus 1 as an effective delivery platform for lung cancer

This is the authors' abstract. We don't add key points for this paper.

Lung cancer is a leading cause of global cancer mortality, highlighting the need of effective, low-toxicity targeted therapies. Virus-like particles (VLPs) are a promising platform due to their virus-mimicry structure, multifunctionality, and safety. We developed integrin αvβ3-targeting VLPs using human bocavirus 1 (HBoV1) VP3 protein for lung cancer-specific doxorubicin (DOX) delivery. And RGD (Arg-Gly-Asp) was inserted into the VP3 VR-I region (residues 80–95) to generate mutant VLPs (M-VLPs). Both wild-type (Wt-VP3) and mutant (M-VP3) proteins were expressed in Escherichia coli ( E. coli ), purified, and self-assembled into uniform nanoparticles. DOX was conjugated via EDC/NHS chemistry to form M-VLPs-DOX. M-VLPs exhibited significantly enhanced uptake in αvβ3-overexpressing A549 (lung cancer) and HUVEC cells compared to wild-type VLPs (Wt-VLPs), but not in low-αvβ3 MCF-7 cells. Under simulated tumor microenvironmental conditions (∼pH 5.5), M-VLPs-DOX released 48% DOX over 24 h, substantially exceeding the 19% at physiological pH 7.4. M-VLPs-DOX demonstrated superior cytotoxicity against A549 cells than free DOX or Wt-VLPs-DOX. M-VLPs-DOX significantly elevated reactive oxygen species (ROS) and DNA damage, promoting apoptosis. ROS subsequently converted DOX into quinone radicals, further amplifying DNA breaks. Uptake occurred primarily via clathrin-mediated endocytosis. In vivo , M-VLPs-DOX maintained stable body weights without significant organ toxicity, unlike free DOX, which caused hepatocyte ballooning degeneration. These results show that RGD-modified HBoV1-VLPs enable integrin αvβ3-mediated tumor targeting, significantly enhancing DOX delivery to lung cancer. This strategy synergistically amplifies oxidative stress and DNA damage, boosting antitumor efficacy while reducing systemic toxicity, supporting the optimization of VLP-based nanocarriers for targeted cancer therapy.