Serious side effects from chemotherapies are the main problem with cancer treatments. To solve these issues, precision cancer nanomedicine based on natural therapeutic materials is developed, which enables specifically apoptosis by interacting with genetic mutation in cancer cells, while leaving normal cells unaffected. Here, we report a novel nanomedicine (CuQDA/IO@HA) composed of hyaluronic acid (HA) / copper ion (Cu(II))-chelated dextran-aldehyde (DA)-quercetin (Q) with dual targeting for synthetic lethal therapy. The CuQDA/IO@HA prepared using a ratio of metal/Q at 0.5:1 resulted in a stable particle structure with uniform particle distribution. The CuQDA/IO@HA can specifically target and induce specific cytotoxicity in BRCA-mutant cancer cells in vitro. Combination treatment with CuQDA/IO@HA and magnetic navigation can induce poly (ADP-ribose) polymerase (PARP) inhibition and DNA damage in BRCA-mutant triple-negative breast cancer (TNBC) via CD44 targeting. The dual-targeting CuQDA/IO@HA can extend the median survival of the BRCA-mutant xenograft mice from 34 to 61 days in comparison to Q treatment alone in vivo, which is attributed to the significant increase in γH2AX, leading to significant apoptosis. More importantly, the CuQDA/IO@HA displayed biocompatibility and no obvious side-effect in normal organs. These results demonstrate the promising potential of integrating natural and metal ions into a nanomedicine that can provide precision medicine through synthetic lethality.