From cell-SELEX to tissue-SELEX for targeted drug delivery and aptamer nanomedicine.

Aptamers are nucleic acid-based ligands that can selectively bind to target molecules. Because of their unique target-binding properties, the use of aptamers for targeting cell surface molecules has attracted broad research interest. The field has evolved from selecting aptamers against purified surface proteins to using whole cells (cell-SELEX) as targets. To further advance the field, the concept of tissue-SELEX was later proposed to ensure that selected aptamers possess optimal binding properties in more native in vivo environments. In this article, we review recent progress made for tissue-SELEX, covering methods including tissue slide-based SELEX, morph-X-SELEX, ex vivo-SELEX, and microfluidic tissue-SELEX. The target tissues include cornea, breast, ovary, lung, cardiac and thyroid tissues. For the diseases targeted, cancer is the most extensively studied followed by cardiomyopathies and vascular conditions. The advantages of each method are discussed and potential limitations are also critically reviewed. Applications of tissue- or in vivo-SELEX-derived aptamers in drug delivery include local administration for ocular diseases and systemic administration for lung cancer. Finally, future directions are discussed, emphasizing the need for systematic comparative studies to evaluate cell-SELEX and tissue-SELEX derived aptamers, using antibodies as benchmarks to guide the development of clinically relevant therapeutic applications.