Targeting severe acidity for tumor-activatable Interleukin-2 therapy.

Interleukin-2 (IL-2) is a cytokine with curative potential in cancer immunotherapy, but its clinical use is limited by a narrow therapeutic window. Traditional strategies such as polarizing receptor binding or fusing IL-2 with Fc (IL-2-Fc) improve pharmacokinetics and immune selectivity, but systemic toxicity remains a key challenge, while covalent prodrug designs may compromise potency and restrict applicability. Here, we present a non-covalent approach using clinically validated ultra pH-sensitive (UPS) polymers to enable tumor-specific IL-2 activation. The UPS(5.3)/IL-2-Fc nanoparticle remains stable at physiological pH, minimizing receptor binding in normal tissues, but dissociates and restores IL-2 activity in severely acidic tumor environments (pH < 5.3). This pH-triggered activation reduces systemic toxicity, resulting in over 100-fold reduction in circulating interferon-γ and prevention of vascular leak syndrome, while preserving antitumor efficacy. Mechanistically, the protective effect relies on both pH-dependent shielding and macrophage clearance. This bioengineering strategy offers a generalizable framework for immune cytokine therapy.