ShiYi Zuo et al. developed tetrasulfide-bond-conjugated cabazitaxel (CTX) dimeric prodrug nanoassemblies (DPNAs), demonstrating that tetrasulfide bonds are crucial for enhancing the stability, blood circulation, and tumor accumulation of DPNAs. The study found that γ-4S-2CTX NPs, with their superior self-assembly stability and high responsiveness to reductive conditions, resolved the efficacy-safety paradox of DPNAs. The "add fuel to the flames" strategy, which involves replenishing exogenous reducing agents, further enhanced the therapeutic efficacy of these DPNAs by intensifying the reductive stress at tumor sites. This strategy significantly improved the anti-tumor efficacy of γ-4S-2CTX NPs while maintaining good safety profiles. The study highlights the potential of tetrasulfide bonds in constructing intelligent DPNAs and provides a promising platform for enhancing cancer therapy.ShiYi Zuo et al. developed tetrasulfide-bond-conjugated cabazitaxel (CTX) dimeric prodrug nanoassemblies (DPNAs), demonstrating that tetrasulfide bonds are crucial for enhancing the stability, blood circulation, and tumor accumulation of DPNAs. The study found that γ-4S-2CTX NPs, with their superior self-assembly stability and high responsiveness to reductive conditions, resolved the efficacy-safety paradox of DPNAs. The "add fuel to the flames" strategy, which involves replenishing exogenous reducing agents, further enhanced the therapeutic efficacy of these DPNAs by intensifying the reductive stress at tumor sites. This strategy significantly improved the anti-tumor efficacy of γ-4S-2CTX NPs while maintaining good safety profiles. The study highlights the potential of tetrasulfide bonds in constructing intelligent DPNAs and provides a promising platform for enhancing cancer therapy.