Click-Engineered Magnetic Fusogenic Cell-Derived Nanocarriers for Enhanced Magnetic-Field-Assisted Drug Delivery

Background Cell membrane-derived nanoparticles (NP) have emerged as a transformative platform in nanomedicine, offering unique advantages for therapeutic delivery and immune modulation. By harnessing the native biological properties of source cells such as red blood cells, platelets, and cancer cells, these biomimetic NP exhibit prolonged circulation, enhanced biocompatibility, and specific targeting capabilities. Membranes retain functional proteins and receptors, enabling precise interfacing with biological environments and providing inherent ability to evade immune detection and to interact with target tissues. Hybrid and engineered membrane platforms that integrate components of different origins (e.g. cell-derived and inorganic NP) hold strong potential for next-generation targeted therapies in oncology, as they can synergistically combine the advantages of both biological and inorganic components. Therefore, we proposed a new NP design based on biomimetic fusogenic nanomembranes decorated through click chemistry with iron oxide (IO) NPs for enhanced homotypic targeting and chemotherapeutic drug delivery under magnetic guidance in different in vitro models of non-small cell lung cancer. Results Our findings present an efficient preparation of a hybrid nanoplatform (magFSMs), based on nanomembranes and IO NPs coupled through strain-promoted azide-alkyne click chemistry (SPAAC) reaction. Our system preserved the magnetic properties of IO NPs as well as the homotypic targeting capabilities of the parental cancer cell membranes. This was evaluated both in adherent cell mono and co-cultures as well as in 3D heterotypic spheroids where magFSMs exhibited preferential recognition for tumoral cells. Our nanoplatform also showed versatile drug-loading capacity, as proved by the incorporation of different small anticancer molecules like carboplatin and doxorubicin, leading to enhanced antitumor activity compared with free drugs. Moreover, those observations were also preserved and even increased in lung cancer spheroids under magnetic guidance, underscoring the feasibility of using magFSMs as magnetically guided drug-delivery nanocarriers. Conclusions MagFSMs prepared within this work has been successfully employed as anticancer nanosystem in several in vitro models of lung cancer, representing a promising tool in personalized and targeted nanomedicine. Our results support the potential of magFSMs as a modular, biomimetic, and magnetically responsive drug-delivery platform, encouraging us to further explore their applicability in additional disease models and to expand their evaluation toward more complex in vivo scenarios.