Dual-responsive magnetic vortex nanorings co-deliver lenvatinib and localized heat for synergistic activation of antitumor immunity

Hepatocellular carcinoma (HCC) presents significant treatment challenges, primarily due to its ability to suppress immune responses. Lenvatinib (LT), approved as a first-line therapy for HCC, modulates the immune microenvironment by reducing PD-L1 expression and decreasing the infiltration of regulatory T cells (T_regs) within the tumor. However, the low immunogenicity of HCC and high toxicity of LT often undermine its effectiveness. To address these challenges, polydopamine (PDA)-coated ferrimagnetic vortex-domain iron oxide nanorings (FVIO@PDA) were engineered to respond to both acidic conditions and magnetic fields, facilitating the simultaneous delivery of the drug (LT) and a physio-therapeutic heat modality. The dual-responsive nature of FVIO@PDA ensures a controlled and synergistic release of LT, activated by acidic tumor microenvironments and the heat produced by an alternating magnetic field (AMF). In a subcutaneous Hepa1–6 HCC model, LT-loaded FVIO@PDA-PEG (denoted as LT-loaded FPP)-mediated magnetic hyperthermia significantly increased the levels of cytotoxic T lymphocytes, showing an approximate 3.86-fold increase compared to the control groups. This combination of LT and magnetic hyperthermia also reduced Treg populations to 1.4 %, synergistically triggering a robust antitumor immune response. Additionally, it altered cytokine profiles, reducing the secretion of the immunosuppressive cytokine IL-10 to 0.41 times that of control levels, while increasing the secretion of pro-inflammatory cytokines IFN-γ and TNF-α by 3.25 and 4.34 times, respectively. Furthermore, LT-loaded FPP-mediated magnetic hyperthermia exhibits superior anti-tumor activity compared to either treatment alone. These results highlight the promise of combining LT with FPP-mediated immunogenic magnetic hyperthermia as a potent therapeutic strategy for HCC, offering a more effective approach to modulate the immune environment and enhance antitumor efficacy.

Statement of significance

Lenvatinib (LT) is a selective multi-targeted tyrosine kinase inhibitor used for patients with unresectable HCC who have not previously undergone systemic therapy. LT's immunomodulatory effects alone are often insufficient to induce an effective immune response, and treatment outcomes continue to be unsatisfactory. We developed FVIO@PDA for the delivery of LT and localized heat. FVIO@PDA allowed for controlled release of LT, triggered by the acidic tumor microenvironment and the heat generated under an AMF. LT combined with magnetic hyperthermia increased CTLs, reduced T_regs, decreased immunosuppressive cytokines, and elevated pro-inflammatory ones, collectively initiating a strong antitumor immune response. LT combined with magnetic hyperthermia showed superior antitumor effect compared to either treatment alone.