Updated project metadata. Loss-of-function mutations in the homotrimeric serine protease HTRA1 cause cerebral vasculopathy. Here, we show that disease-causing mutations targeting the protomer-protomer interface impair trimerization. Focusing on a prototypical interface mutation (R274Q), we designed an HTRA1 variant that complemented pathogenic HTRA1 and reconstituted its multimeric assembly and enzymatic activity in vitro. Genetic experiments in Htra1R274Q mice further demonstrated that expression of this protein-based corrector in trans was sufficient to stabilize HTRA1-R274Q and restore the cerebrovascular proteome. As an alternative approach to achieve repair of pathogenic interface mutants, we generated supramolecular chemical ligands that shifted the monomer-trimer equilibrium by stabilizing proteolytically active trimers. Moreover, we identified a peptidic ligand that activated HTRA1 monomers. Collectively, our findings open novel perspectives for tailored protein repair strategies.