A Protease- and pH-Gated, Locally Activated Nanobody–Fc for Solid Tumors: Core Hypothesis and Conditional Outlook

We hypothesize a practical, testable route to intensify local antitumor action while preserving safety: a single masked nanobody–substrate–fragment crystallizable (Nb–Sub–Fc) confined by an injectable, biodegradable hydrogel. The construct encodes a sequential logical AND gate: a tumor-associated protease (e.g., membrane-type-1 matrix metalloproteinase, MT1-MMP) first unmasks antigen binding, and a mildly acidic threshold (~6.7) then permits fragment crystallizable (Fc) effector engagement—concentrating activation at invasive rims while minimizing systemic exposure. If safety margins hold, analytics remain robust, and manufacturing and linker chemistry are available and mature, a conditional expansion to a stage-/niche-responsive set of pre-qualified Nb–Sub–Fc variants could broaden coverage across heterogeneous niches. For highly heterogeneous lesions, a co-primary alternative—Hydrogel-Programmed Fc Confinement—keeps full Fc competence confined to the hydrogel while allowing protease-dependent antigen binding in surrounding tissue.