Universal Albumin Drugs‐Cored Spherical Nucleic Acid (ad‐SNA) Platform for Targeted Drug Delivery

Abstract Albumin‐based drug delivery system, exemplified by FDA‐approved treatments like Abraxane, have demonstrated significant potential in cancer therapy. However, albumin carriers still suffer from poor tumor‐targeting capability, leading to low efficacy and systemic side effects on healthy cells in applications. Here, we report a general method for modification of albumin drugs by aptamer coating shell that are hydrophobically inserted into the albumin surface, for constructing albumin drugs‐cored spherical nucleic acid (adSNA). This adSNA platform allows for the versatile loading of various therapeutic agents, including chemotherapy drugs, polyphenols, cuproptosis inducers, and near‐infrared (NIR) photosensitizers, enabling targeted tumor delivery. Compared with covalent method, the hydrophobic insertion method has been proven to be of greater simplicity, higher aptamer‐grafting efficiency, superior tumor‐targeting capabilities, and comparable stability under physiological conditions. In a proof‐of‐concept study, we delivered NIR‐II photothermal agents and heat shock protein inhibitors for tumor‐specific mild photothermal therapy. Compared to traditional photothermal therapy (PTT), this approach utilizes NIR‐II PTT agents to achieve greater tissue penetration while downregulating heat shock proteins in tumor cells, resulting in precise thermal ablation at lower temperatures. In addition, the adSNAs are straightforward to synthesize and scalable for large‐scale production, offering significant potential to advance the development of clinical targeted drugs.