Steric Hindrance-Engineered Redox-Responsive Disulfide-Bridged Homodimeric Prodrug Nanoassemblies for Spatiotemporally Balanced Cancer Chemotherapy

The rational design of tumor-responsive prodrug nanoassemblies requires precise control over systemic stability and site-specific activation. While α-position disulfide bonds are advantageous for rapid response to redox conditions, they also risk premature drug leakage during circulation. This study introduces a steric hindrance-guided approach to engineer disulfide-bridged podophyllotoxin homodimeric prodrugs for spatiotemporal controlled delivery. By monomethyl or dimethyl substitution of the carbon atoms adjacent to the α-disulfide bond, we can modulate steric hindrance. Excessive hindrance destabilizes the nanoassemblies and slows effective drug release, while moderate hindrance (monomethyl modification) enhances pharmacokinetic properties and promotes selective tumor activation. In vivo studies indicate that monomethyl-modified prodrug nanoassemblies exhibit superior antitumor efficacy and reduced off-target toxicity compared to PPT solution. This work underscores the importance of steric hindrance in optimizing prodrug nanoassembly stability and tumor-specific activation, offering a comprehensive strategy for redox-responsive nanomedicines.