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Herein, we report an acid\u2010activatable nucleic acid nano\u2010prodrug based on rolling circle replication, which directly integrates a large number of amplified Cas12\/crRNA ribonucleoproteins (RNPs) and antisense oligonucleotides (ASOs) with minimal excipients, achieving tumor\u2010specific activation for PDAC combined gene therapy. The nano\u2010prodrug is assembled from a polymeric crRNA chain conjugated with Cas12a (Pro\u2010RNPs) and a polymeric ASOs chain (Pro\u2010ASOs)\u2014the latter incorporating AS1411 aptamers for cancer targeting and HhaI cleavage sites for stimuli\u2010responsive release\u2014while being surface\u2010loaded with acid\u2010degradable polymer\u2010coated HhaI enzymes. Upon PDAC uptake, the nano\u2010prodrug is activated within acidic lysosomes through degradation of HhaI enzymes\u2019 polymer coating. HhaI cleaves specific recognition sites while overexpressed ribonuclease H hydrolyzes the RNA strand in DNA\u2010RNA heteroduplexes. These combined cleavage events disrupt the nano\u2010prodrug, enabling efficient co\u2010release of ASOs and Cas12a\/crRNA RNPs for precise gene silencing and editing. In vivo studies in PDAC\u2010bearing mice demonstrate potent antitumor activity with minimal systemic toxicity or immunogenicity, presenting a promising strategy for precision gene therapy in pancreatic cancer.<\/jats:p>","DOI":"10.1002\/adma.75257","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T10:06:50Z","timestamp":1790849210000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Acid\u2010Activatable Rolling Circle Replication\u2010Based Nucleic Acid Nano\u2010Prodrug for Combined Gene Therapy of Pancreatic Cancer"],"prefix":"10.1002","author":[{"given":"Xun","family":"You","sequence":"first","affiliation":[{"name":"State Key Laboratory of Synthetic Biology Frontiers Science Center for Synthetic Biology Key Laboratory of Systems Bioengineering (MOE) School of Synthetic Biology and Biomanufacturing Tianjin University  Tianjin P. R. 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