Background: Traditional sutures often fail to meet the complex demands of wound closure across diverse anatomical environments. This study introduces a novel drug-eluting, multiscene absorbable biological suture derived from decellularized fish swim bladder, designed to address limitations in mechanical performance, pH resistance, and foreign body reactions. Methods: Swim bladders were decellularized, microdissected into 0.3-mm strips, and functionalized with rapamycin (RAPA) or necrostatin-1 (NEC-1) via hyaluronic acid/polyvinyl alcohol coatings. Sutures were evaluated for cytotoxicity [human umbilical vein endothelial cell (HUVEC) assays], mechanical properties (tensile/acid/alkali resistance), and efficacy in rat models of venous/arterial, intestinal, gastric, and abdominal wall closures ( n = 3/group). Histological (hematoxylin and eosin, immunofluorescence) and scanning electron microscopy analyses were performed. Results: The NEC-1 sutures demonstrated superior tensile strength (hydrated: 2.1 ± 0.3 N vs. RAPA: 1.8 ± 0.2 N, CTL: 1.5 ± 0.2 N; P <0.05) and maintained structural integrity in both acidic (pH 1.0) and alkaline (pH 8.0) environments for 7 days. In vitro , drug-loaded sutures significantly inhibited HUVEC proliferation by 40% ( P = 0.0096) without inducing apoptosis. In vivo evaluations across venous, arterial, intestinal, gastric, and abdominal wall closures revealed that NEC-1 sutures markedly reduced foreign body reactions, exhibiting the smallest capsule area (0.12 ± 0.03 mm ² vs. CTL: 0.35 ± 0.05 mm ² ; P <0.0001) and 58% fewer CD68 + macrophages compared to controls ( P = 0.0015). All suture types achieved successful leak-free wound closures, with NEC-1 showing particularly strong suppression of neovascularization (CD31 + vessels: 12 ± 3 vs. CTL: 28 ± 5; P = 0.0001). The RAPA sutures also showed significant improvements over controls but were intermediate in performance between NEC-1 and uncoated CTL sutures. Mechanical testing confirmed that both drug-loaded variants (RAPA and NEC-1) maintained higher strength than CTL sutures under both dry and hydrated conditions, while histological analyses demonstrated progressive reductions in inflammatory markers (CD45 +, PCNA +, cleaved caspase 3 + cells) with drug-functionalized sutures. Conclusion: Swim bladder-derived sutures demonstrate universal applicability, staged drug release, and significant reductions in inflammatory responses, offering a promising alternative for multitissue surgical repairs. Graphic The process of making suture and summarizing the cross-tissue analysis protocol. A: Surgical extraction and processing workflow. ① Tissue harvest from fish. ② The swim bladder undergoes decellularization treatment. ③ Microdissection into standardized strips. ④ The swim bladder is processed to create a drug-carrying, multiscene, absorbable biological suture. B: Fish swim bladder suture is used to stitch various organs. (i) Inferior vena cava and infrarenal abdominal aorta. (ii) Small intestine. (iii) Stomach. (iv) Abdominal wall.