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Pancreatic cancer stands out as a recognized intractable tumor due to its high malignancy and mortality rates, which are largely attributed to the insensitivity of current clinical chemotherapies or multidrug-resistance. Combinatorial chemo and gene therapy that integrates different therapeutic targets, may increase the chemosensitivity of pancreatic cancer and synergistically enhance the antitumor efficacy. However, conventional co-delivery of gene and chemo drugs is intensively dependent on complex nanoparticle delivery systems, thus would be limited by unstable drug packaging, nonspecific biodistribution, and biosafety problem. Herein, we rationally designed an epidermal growth factor-receptor (EGFR)-targeted and gemcitabine-incorporated oligonucleotide (termed as chemogene) with anti-Bcl-2 sequence, which achieves simple and precise integration of gemcitabine into a gene regulative agent, as well as the EGFR-targeted delivery for pancreatic cancer therapy. Through solid-phase synthesis, gemcitabine, as the first-line chemodrug for pancreatic cancer, is introduced to the antisense oligonucleotide to replace all cytosine nucleosides to obtain the gemcitabine-integrated chemogene (Ge-ASOBcl-2). Thereafter, Ge-ASOBcl-2 is covalently coupled with EGFR nanobody to construct the final targeted chemogene without any exogenous carriers. Notably, this nanobody-conjugated chemogene exhibits remarkable tumor targeting capability and antitumor effects both in vitro and in vivo, which initiates a first step toward the application of combinatorial chemo and gene therapy for future pancreatic cancer treatment.
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