Dual Conversion‐Enabled Gelatin/CuS Platform for Synergistic Photothermal‐Enhanced Chemodynamic Therapy With Precision Cancer Targeting

Low drug permeability remains major obstacles to effective tumor therapy, often leading to poor intratumoral drug distribution, limited tumor cell killing, and high recurrence rates. To address poor drug permeability and single-mode responsiveness in combined photothermal-chemodynamic-chemotherapy, a pH-/enzyme-/NIR-responsive gelatin/CuS nanocluster (icluster) is developed as a versatile drug delivery platform. Using DOX and JQ-1 as model drugs, the drug-loaded iclusters are synthesized via electrostatic self-assembly of hyaluronic acid and dimethyl maleic anhydride-modified gelatin (HA-GelDMA) with drug-loaded CuS nanoflower. In the mildly acidic tumor microenvironment enriched with MMP-2, this system triggers a dual transformation mechanism of size and charge: after achieving efficient tumor enrichment as large-sized iclusters (-37.2 mV, 301.5 nm), it decomposes into small-sized positively charged nanoparticles (+14.7 mV, 173.7 nm), significantly improving tumor penetration and cellular uptake. After 5 days of treatment, tumor spheroids are nearly fully disintegrated. The icluster achieves high photothermal conversion efficiency (10.7%) and generates hydroxyl radicals for chemodynamic therapy via the Fenton-like reaction. In vitro, with H₂O₂ and NIR, DOX- and JQ1-loaded iclusters significantly inhibit 4T1 and SW1353 cells. In vivo, JQ1-icluster suppresses tumor growth with high specificity and retention. This work presents a promising multi-responsive nanoplatform capable of precise delivery and deep penetration.