Overcoming multidrug resistance through fucoidan from molecular mechanisms to nanomedicine applications.

Multidrug resistance (MDR) remains a major obstacle to effective chemotherapy due to apoptosis inhibition, overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp), which expel anticancer drugs and lower their intracellular concentration. Fucoidan, a sulfated polysaccharide from brown seaweeds, has demonstrated promising anti-MDR activity by downregulating P-gp expression, inhibiting its ATPase activity, and modulating PI3K/Akt and NF-κB signaling. It also induces apoptosis and regulates oxidative stress, inflammation, and immune activity, restoring tumor chemosensitivity. The structure-function determinants, including molecular weight, sulfate density and positioning, and branching, play a key role in governing fucoidan's biological activity and its interactions with cellular targets. These features enable the design of fucoidan-based nanocarriers that co-deliver chemotherapeutics, target tumors via P-selectin binding, and release drugs in response to pH or ROS, thereby helping to overcome efflux and enhance apoptosis in resistant tumors. This review integrates mechanistic evidence linking fucoidan to regulated cell death pathways, highlights advances in fucoidan-enabled nanomedicine, and outlines translational hurdles along with practical routes to standardization and clinical evaluation. Positioning fucoidan as an apoptosis-oriented adjuvant offers a systems-level strategy to re-sensitize multidrug-resistant cancers to therapy.