CD44 Targeting of Cisplatin-Loaded Hyaluronic Acid-Modified Mesoporous Silica Nanoparticles for Lung Adenocarcinoma: Synthesis, Characterization, In Vitro and In Vivo Evaluation

Background/Objectives: Cisplatin (CDDP) is widely used in the treatment of non-small cell lung cancer (NSCLC); however, its clinical efficacy is limited by severe systemic toxicity. Hyaluronic acid (HA) modification enables the targeting of CD44-overexpressing cancer cells, enhances biocompatibility, provides controlled drug release, and prolongs systemic circulation. This study aimed to develop high-molecular-weight hyaluronic acid-modified, cisplatin-loaded mesoporous silica nanoparticles (HA-MSN-CDDP) to selectively target CD44-overexpressing lung adenocarcinoma cells. Methods: HA-MSN-CDDP nanoparticles were synthesized via the sol-gel method and characterized by FTIR, DLS, SEM, and TEM methods. Antitumor efficacy was evaluated using both in vitro and in vivo xenograft lung cancer models in mice. Results: HA modification enabled controlled and sustained release of cisplatin from the HA-MSN-CDDP drug delivery system. Through HA-mediated receptor-dependent endocytosis, the nanoparticles exhibited enhanced cellular uptake and selective cytotoxicity toward CD44-positive cells. HA-MSN-CDDP significantly reduced the cytotoxic, genotoxic, and oxidative stress effects of free cisplatin on healthy cells while markedly enhancing apoptosis in A549-Luc-C8 cells. The system showed excellent hemocompatibility, supporting its potential for intravenous use. In vivo, HA-MSN-CDDP effectively suppressed tumor growth, mitigated lipid peroxidation, and preserved antioxidant enzyme activities (SOD and CAT) in major organs. Histological analyses confirmed reduced cisplatin-induced nephrotoxicity. Conclusions: HA-MSN-CDDP demonstrates strong potential as a targeted chemotherapeutic platform for NSCLC, combining high antitumor efficacy with reduced systemic toxicity.