Polyunsaturated fatty acid-functionalized fucoidan nanoparticles targeting and regulating "tumor ecosystem" for...

Cancer therapy faces challenges due to the complex "tumor ecosystem". To address this, our study constructed nanoparticles (NPs) capable of efficiently targeting and eliminating tumor cells while regulating the microenvironment. Specifically, two polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA) and arachidonic acid (AA), were conjugated with fucoidan (Fu) to form NPs and encapsulated doxorubicin (DOX), termed D@DF and D@AF. Both NPs could directly target tumor cells or indirectly via activated platelets, with the released DOX and PUFAs inducing apoptosis and ferroptosis. Notably, D@DF demonstrated superior anti-tumor and anti-metastatic efficacy in vivo, which could be attributed to the enhanced targeting ability mediated by P-selectin and FATP2. Meanwhile, it was also related to the key microenvironmental signaling molecules (COX-2 and MMP-9) modulating effects of DHA. Collectively, D@DF achieved high tumor cell clearance efficiency and systematic regulation of "tumor ecosystem", providing a new approach for cancer therapy.