Decellularization can reduce the immune barrier of xenotransplantation, but tissue swelling‐caused structural and functional damage remains unsolved, including corneal transparency loss after decellularization. Here, a protective decellularization strategy is developed for the preparation of decellularized porcine cornea (DPC), in which corneas are treated by detergent and endonuclease in the protective medium with 50 mmHg colloid osmotic pressure. A nonrandomized open‐label trial is conducted to evaluate the clinical outcome of lamellar transplantation with DPC versus human donor cornea (HDC) as grafts. Through the protective corneal decellularization, major xenoantigen DNA and α‐gal are efficiently removed, while corneal original structural and transparency characteristics are preserved. Among the 23 patients with DPC transplantation for 12 months, 22 grafts survive without ulcer recurrence or immune rejection, 1 graft demonstrate melting. Compared with HDC grafts, DPC grafts showed early suture loosing, but no complication is observed with timely removal. The epithelial regeneration rate, graft transparency restoration, best‐corrected visual acuity improvement, and mechanical properties achieve equivalent levels compared with that of HDC grafts. Collectively, the results suggest that the porcine cornea through protective decellularization may provide an effective “off‐the‐shelf” substitute of globally‐shortened human donor tissue for lamellar transplantation.

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Human pluripotent stem cells (hPSCs) hold great promise for the treatment of various human diseases. However, their therapeutic benefits and mechanisms for treating corneal endothelial dysfunction remain undefined. Here, we developed a therapeutic regimen consisting of the combination of hPSC-derived corneal endothelial precursors (CEPs) with nicotinamide (NAM) for effective treatment of corneal endothelial dysfunction. In rabbit and nonhuman primate models, intracameral injection of CEPs and NAM achieved long-term recovery of corneal clarity and thickness, similar with the therapeutic outcome of cultured human corneal endothelial cells (CECs). The transplanted human CEPs exhibited structural and functional integration with host resident CECs. However, the long-term recovery relied on the stimulation of endogenous endothelial regeneration in rabbits, but predominantly on the replacing function of transplanted cells during the 3-year follow-up in nonhuman primates, which resemble human corneal endothelium with limited regenerative capacity. Mechanistically, NAM ensured in vivo proper maturation of transplanted CEPs into functional CECs by preventing premature senescence and endothelial-mesenchymal transition within the TGF-β–enriched aqueous humor. Together, we provide compelling experimental evidence and mechanistic insights of simultaneous delivery of CEPs and NAM as a potential approach for treating corneal endothelial dysfunction.