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