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Abstract Amphiphilic self‐immolative polymers (SIPs) can achieve complete degradation solely through one triggerable event, which potentially optimize the blood clearance and uncontrollable/inert degradability for therapeutic nanoparticles. Herein, we report self‐immolative amphiphilic poly(ferrocenes), BP nbs ‐Fc , composed by self‐immolative backbone and aminoferrocene (AFc) side chains as well as end‐capping poly(ethylene glycol) monomethyl ether. Upon triggering by tumor acidic milieu, the BP nbs ‐Fc nanoparticles readily degrade to release azaquinone methide (AQM) moieties, which can rapidly deplete intracellular glutathione (GSH) to cascade release AFc. Furthermore, both AFc and its product Fe 2+ can catalyze intracellular hydrogen peroxide (H 2 O 2 ) into highly reactive hydroxyl radicals (⋅OH), thus amplifying the oxidative stress of tumor cells. Rational synergy of GSH depletion and ⋅OH burst can efficiently inhibit tumor growth by the SIPs in vitro and in vivo. This work provides an elegant design to adopt innate tumor milieu‐triggerable SIPs degradation to boost cellular oxidative stress, which is a promising candidate for precision medicine.
Xu et al. (Fri,) studied this question.