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

ABSTRACT 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) (C ₁₈ PMH), 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.