Tailored "Three-stage booster" nano-extinguisher for synergistic treatment of severe acute pancreatitis by rectifying mitochondrial dysfunction and inhibiting pancreatic autodigestion.

Overcoming the blood-pancreatic barrier to deliver pharmaceuticals to injured pancreatic acinar cells (PACs), rectifying mitochondrial dysfunction, and inhibiting pancreatic autodigestion are critical for treating severe acute pancreatitis (SAP). Herein, a "three-stage booster" Oc-M2M@HMnOCsA nanomedicine was developed, employing HMnO to efficiently encapsulate cyclosporine (cyclosporine (Cyclosporine capsules) capsules) A (CsA), subsequently enveloped with an M2-like macrophage membrane and surface-modified with octreotide (Oc). Initially, the CCR-2 protein-enriched M2-like macrophage membrane-wrapped NPs rapidly and precisely adhere to the highly expressed CCL-2 on the damaged endothelial cells, then migrating trans-endothelially to the injured pancreatic tissue within 1 hour, with sustained high retention at 24 h. Afterwards, Oc specifically binds to the SSTR-2 receptor on PACs, effectively suppressing the secretion of amylase, lipase, and trypsin, while enhancing the cellular internalization efficiency of core HMnOCsA NPs by up to 80 %. Internalized NPs eventually disintegrate in response to an elevated ROS and slightly acidic pathological environment, rapidly depleting ROS and synchronously generating O while promptly releasing loaded CsA to inhibit the aberrant opening of the mPTP, thereby restoring redox homeostasis and rectifying mitochondrial dysfunction. This process subsequently restores Ca homeostasis and prevents the activation of the Cyt-C-Casp-11-Casp-3-GSDME pyroptosis signaling pathway, effectively blocking downstream trypsinogen activation and the inflammatory amplification cascade. Consequently, this nanomedicine decreased the proportion of TUNEL-positive PACs from 40.3 % to 3.9 %, normalized pancreatic function within 24 h of treatment, and improved overall survival from 41.7 % to 91.7 %. This biomimetic nanoformulation may offer a promising upstream therapeutic strategy for the management of SAP in clinical settings. STATEMENT OF SIGNIFICANCE: The deep anatomical positioning of the pancreas, the existence of the blood-pancreatic barrier (BPB), and the lack of precise targeting toward damaged pancreatic acinar cells (PACs) are challenges in the development of drugs for severe acute pancreatitis (SAP). Herein, a biomimetic three-stage booster was constructed, which achieved the first stage of tissue targeting, the second stage of PACs targeting, and the third stage of precision drug delivery in turn through M2 macrophage membrane, octreotide, and cyclosporine (cyclosporine (Cyclosporine capsules) capsules) A -loaded HMnO NPs. This nanovesicle could restore mitochondria function and inhibit the pancreatic autodigestion, collectively restoring pancreatic function. This biomimetic nanoformulation may offer a promising upstream therapeutic strategy for the management of SAP in clinical settings.