In Situ Formation of Croconaine Structures as Covalent Crosslinkers for Structurally Stabilized Photothermal Nanoparticles

ABSTRACT Photothermal therapy (PTT) has attracted increasing interest for cancer treatment owing to its high spatial selectivity and minimal invasiveness. Organic photothermal dyes typically exhibit high photothermal conversion efficiencies and favorable biocompatibility; however, they are most commonly incorporated into nanocarriers via physical encapsulation or noncovalent interactions. Such loading strategies are prone to dye leakage under physiological conditions and often induce uncontrolled molecular aggregation. The resulting π–π stacking can cause hypsochromic shifts, weakening near‐infrared (NIR) light absorption and reducing photothermal efficiency within biologically relevant spectral windows. Here, we report a covalent locking strategy for constructing structurally stabilized photothermal nanoparticles via in situ covalent crosslinking of croconic acid within an amphiphilic block copolymer matrix. Dehydration‐induced covalent locking immobilizes photothermal units in a crosslinked core, suppressing dye dissociation and aggregation. The resulting nanoparticles exhibit enhanced colloidal, thermal, and photostability while maintaining strong NIR absorption and high photothermal conversion efficiency of 72.4%. Consequently, they demonstrate efficient photothermal performance in vitro and pronounced antitumor efficacy in vivo with minimal systemic toxicity. Overall, this work establishes covalent crosslinking as a general structural design strategy for organic photothermal nanomaterials, providing a robust and versatile platform for photothermal cancer therapy.