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

Combination therapy is emerging as a critical strategy in the pursuit of synergistic effects in cancer treatment due to the complicated pathogenesis and rapid progression of tumors. However, the limited tumor accumulation and penetration of nanomedicines within tumors are increasingly recognized as significant barriers to achieving the expected efficacy due to the complex physiological barriers of a solid tumor microenvironment. A size-shrinkable multistage nanocomposite CuS-DOX@MA/Gel was successfully fabricated by conjugating doxorubicin (DOX) onto copper sulfide nanoparticles (CuS NPs) through an imine bond (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 initial 180.1 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 effective retention around the tumor periphery but also significantly enhanced deep penetration into both multicellular spheroids and solid tumors. Simultaneously, the MMP-2-dependent release of 3-MA could block autophagosome formation and augment the sensitivity of chemotherapy. Then, pH sensitivity was confirmed, and CuS-DOX@MA/Gel exhibited proficient drug release in vitro upon exposure to acidic conditions. CuS NPs exhibited the capacity to absorb near-infrared (NIR) light, thereby enabling a sophisticated photodynamic and photothermal therapy that synergistically enhanced chemotherapy. In vivo results demonstrated that CuS-DOX@MA/Gel treated with intravenous administration and an 808 nm laser irradiation achieved excellent tumor inhibition efficacy on 4T1 tumor-bearing mice. This size-adjustable multifunctional strategy should be a potential candidate in the anticancer field due to the outstanding synergistic therapeutic effect.