Bioinspired IgM‐Mimetic Polyvalent Aptamer‐Albumin Nanoplatform for Targeted Intravesical Therapy of Bladder Cancer

Albumin-based therapeutics are widely used in cancer treatment for their biocompatibility and hydrophobic drug-loading capacity, but their efficacy is often limited by poor target specificity and weak binding affinity. Inspired by the multivalent and cooperative binding of immunoglobulin M (IgM), we developed a biomimetic tandem Y-shaped Sgc8 aptamer-albumin delivery system (TYS-HSA). By grafting two hydrophilic aptamers onto each hydrophobic C18 side chain of poly(maleic anhydride-alt-1-octadecene) (C₁₈PMH), we constructed well-defined multivalent aptamer units that self-assembled with human serum albumin (HSA) into an IgM-like ligand corona. Quantitative analysis revealed a high ligand valency of approximately 240 aptamers per TYS-HSA nanoparticle, which, combined with its tandem Y-shaped topology, enables cooperative multivalent recognition. This design achieved high-affinity, stable target recognition while maintaining strong loading capacity for hydrophobic drugs such as paclitaxel. Compared with lower-valency conjugates (MS-HSA, approximately 95 aptamers per nanoparticle), TYS-HSA showed enhanced target binding, prolonged cellular retention, and potent antitumor efficacy after a single intravesical administration in an orthotopic bladder cancer model. With broad drug compatibility and excellent physiological stability, this platform offers a promising and generalizable strategy for the targeted design of albumin-based nanomedicines.