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Anticancer peptides present a promising avenue as alternative therapeutic agents; however, they encounter significant drawbacks, including susceptibility to proteolytic degradation and constrained selectivity toward tumor. Herein, a\u00a0few\u2010shot peptide screening strategy is developed, yielding identification of RT2 (tumor\u2010lytic peptide) and E16 (ionic\u2010responsive self\u2010assembling peptide). Their fusion E16\u2010RT2 (ER) is engineered, exhibiting\u00a0175% enhanced tumor\u2010selective cytotoxicity\u00a0and cancer membrane targeting. By leveraging the dual functionality of ER, an injectable hydrogel encapsulating doxorubicin is developed, enabling gradient dynamics for tumor\u2010specific drug release and sustained therapeutic efficacy (&gt;9 d). Moreover, there is no systemic\/organ toxicity in murine models dosed with the therapeutic network. The potential mechanism is proposed: charge\u2010guided ER localization disrupts cancer membrane integrity, enabling therapeutics influx while sparing healthy cells, coupled with network degradation kinetics ensuring prolonged drug retention. This rational design paradigm establishes a clinically translatable platform combining tumor\u2010perturbing peptides with smart biomaterials, effectively overcoming limitations of conventional agents. The demonstrated \u201csafety\u2010efficacy\u201d profile positions this approach as a viable strategy for cancer treatment.<\/jats:p>","DOI":"10.1002\/adhm.202501753","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T08:17:00Z","timestamp":1748333820000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Few\u2010Shot Identification of Active Therapeutic Peptide Networking with Gradient Dynamics against Cancer"],"prefix":"10.1002","volume":"14","author":[{"given":"Runzhi","family":"Xia","sequence":"first","affiliation":[{"name":"China\u2010Japan Friendship Hospital (Institute of Clinical Medical Sciences) Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 100029 P. R. China"},{"name":"Engineering Research Center of Advanced Rare Earth Materials (Ministry of Education) Department of Chemistry Tsinghua University  Beijing 100084 P. R. 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