Enzyme/pH Dual-Responsive Size-Shrinkable Nanocomposites for Tumor Penetration and Enhanced Multimodal Cancer Therapy

Combinationtherapy is emerging as a critical strategy in the pursuitof synergistic effects in cancer treatment due to the complicatedpathogenesis and rapid progression of tumors. However, the limitedtumor accumulation and penetration of nanomedicines within tumorsare increasingly recognized as significant barriers to achieving theexpected efficacy due to the complex physiological barriers of a solidtumor microenvironment. A size-shrinkable multistage nanocompositeCuS-DOX@MA/Gel was successfully fabricated by conjugating doxorubicin(DOX) onto copper sulfide nanoparticles (CuS NPs) through an iminebond (CuS-DOX), which endowed the system with pH-triggered cargo release.Subsequently, a capping layer composed of metalloproteinase-2 (MMP-2)degradable gelatin and autophagy inhibitor 3-methyladenine (3-MA)was grafted onto CuS-DOX through glutaraldehyde-mediated cross-linking.The size of CuS-DOX@MA/Gel can be effectively reduced from the initial180.1 nm to small-sized CuS NPs of about 57.2 nm in response to MMP-2.This process of reducing particle size not only facilitated effectiveretention around the tumor periphery but also significantly enhanceddeep penetration into both multicellular spheroids and solid tumors.Simultaneously, the MMP-2-dependent release of 3-MA could block autophagosomeformation and augment the sensitivity of chemotherapy. Then, pH sensitivitywas confirmed, and CuS-DOX@MA/Gel exhibited proficient drug release in vitro upon exposure to acidic conditions. CuS NPs exhibitedthe capacity to absorb near-infrared (NIR) light, thereby enablinga sophisticated photodynamic and photothermal therapy that synergisticallyenhanced chemotherapy. In vivo results demonstratedthat CuS-DOX@MA/Gel treated with intravenous administration and an808 nm laser irradiation achieved excellent tumor inhibition efficacyon 4T1 tumor-bearing mice. This size-adjustable multifunctional strategyshould be a potential candidate in the anticancer field due to theoutstanding synergistic therapeutic effect.