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Surgical resection often leaves residual lesions that lead to tumor recurrence and high mortality across various cancer types, a challenge that is particularly pronounced in oral squamous cell carcinoma. Herein, we developed a sprayable hydrogel loaded with fusion cellular vesicles (Fus-CVs) and characterized its structural and mechanical properties for the prevention of postoperative tumor recurrence. Fus-CVs co‑express PD‑1 to engage PD‑L1 on tumor cells and CD36 to competitively bind oxidized lipids in the tumor microenvironment, thereby effectively reversing T cell exhaustion and restoring T cell effector function. Additionally, the sprayable hydrogel, formed by crosslinking sodium alginate (SA) with the ionic solution (calcium chloride, CaCl₂; manganese chloride, MnCl₂), enables sustained local delivery of Fus‑CVs to potentiate T cell‑mediated killing of residual tumor cells.

In vitro experiments and primary tumor model confirmed that Fus‑CVs specifically achieve dual targeting of PD-L1 on tumor cells and oxidized lipids in the tumor microenvironment, reverse T cell exhaustion and achieve combination therapy. In an established postoperative recurrence mouse model, the SA solution containing Fus-CVs and the ionic solution could be co-sprayed to rapidly form a conformal, uniform and stable layer on irregular tissue surfaces, enabling sustained local release of Fus-CVs and achieve effective tumor recurrence suppression.

Fus‑CVs-loaded sprayable hydrogel not only achieves dual functionality in immune checkpoint blockade and lipid metabolic regulation but also offers localized controlled release, and reduced systemic toxicity, thereby presenting a clinically translatable strategy for postoperative recurrence prevention.