Dual-stimuli magnetic drug nanoparticles for chemoimmunotherapy: Magnetically driven, charge-reversal enhanced tumour penetration and pH-triggered drug release

Poor intratumoral penetration remains a major obstacle to effective chemotherapy, caused by dense extracellular matrices, high interstitial pressure, and abnormal vasculature. Magnetic nanoparticle (NP)-mediated drug delivery provides spatial control, but existing systems suffer from low drug loading, weak responsiveness to tumour microenvironments, and limited penetration. Here, we report for the first time a self-assembled nanoplatform in which ultrasmall Fe₃O₄ NPs are evenly distributed within a carrier-free doxorubicin (DOX) core and surface-modified with glycol chitosan (Fe₃O₄-DOX@GC NPs). This unique architecture simultaneously achieves ultra-high drug loading (69%) and markedly enhances responsiveness to external magnetic fields, addressing two long-standing challenges in magnetic nanomedicine. In addition, tumour acidity triggers surface charge reversal from negative to positive, promoting efficient cellular uptake. In 3D tumour spheroids, dual static and alternating magnetic fields increased DOX retention by 2.02-fold compared with static fields alone. In vivo, magnetic guidance produced a 6.3-fold increase in tumour accumulation and a 55% tumour volume reduction relative to free DOX. Importantly, the nanoplatform also activated antitumour immunity, significantly expanding cytotoxic T cells and antitumoral macrophages. This first-in-class dual chemotherapeutic–immunotherapeutic nanoplatform establishes a powerful strategy to overcome tumour penetration barriers while reshaping the immune microenvironment for improved cancer therapy. • First demonstration of uniformly distributed magnetic cores in carrier-free drug NPs • 6853 Fe₃O₄ NPs uniformly embedded in each DOX NP for strong magnetism • Nanomedicine combines high loading, magnetic control & deep tumour penetration. • Magnetic guidance enhances tumour DOX delivery 6.3-fold over free DOX in vivo. • Fe₃O₄-DOX@GC NPs synergise chemotherapy with immunotherapy in vivo.