Ligand Regulation Strategy to Modulate ROS Nature in a Rhodamine-Iridium(III) Hybrid System for Phototherapy.

The efficacy of photodynamic therapy (PDT) is highly dependent on the photosensitizer features. The reactive oxygen species (ROS) generated by photosensitizers is proven to be associated with immunotherapy by triggering immunogenic cell death (ICD) as well. In this work, we establish a rhodamine-iridium(III) hybrid model functioning as a photosensitizer to comprehensively understand its performance and potential applications in photodynamic immunotherapy. Especially, the correlation between the ROS generation efficiency and the energy level of the Ir(III)-based excited state (T1'), modulated by the cyclometalating (C∧N) ligand, is systematically investigated and correlated. We prove that in addition to the direct population of the rhodamine triplet state (T1) formed through the intersystem crossing process with the assistance of a heavy Ir(III) metal center, the fine-tuned T1' state could act as a relay to provide an additional pathway for promoting the cascade energy transfer process that leads to enhanced ROS generation ability. Moreover, type I ROS can be effectively produced by introducing sulfur-containing thiophene units in C∧N ligands, providing a stronger M1 macrophage-activation efficiency under hypoxia to evoke in vivo antitumor immunity. Overall, our work provides a fundamental guideline for the molecular design and exploration of advanced transition-metal-based photosensitizers for biomedical applications.

68Ga-Labeled Magnetic-NIR Persistent Luminescent Hybrid Mesoporous Nanoparticles for Multimodal Imaging-Guided Chemotherapy and Photodynamic Therapy.

Featured with a zero-autofluorescence background, superior signal-to-noise ratio, high sensitivity, and deep penetration ability, near-infrared persistent luminescence nanoparticle (NIR-PLNP)-based multimodal nanoprobes show great potential for full-scale noninvasive cancer diagnosis. However, direct synthesis of NIR-PLNP-based multimodal nanoprobes with high drug loading capacity to meet growing cancer theranostic demands remains a challenge. In this work, multifunctional hybrid mesoporous nanoparticles (HMNPs) that integrate NIR-PLNPs (Ga2O3:Cr3+, Nd3+), magnetic nanoparticles (Gd2O3), and radionuclides (68Ga) are designed and constructed via a large-pore (mesoporous silica nanoparticle) MSN-templated strategy. The ingenious composition design endows HMNPs with rechargeable NIR-PL, superior longitudinal relaxivity, and excellent radioactivity, making these versatile nanoparticles available for long-term in vivo NIR-PL imaging, magnetic resonance imaging (MRI), and positron emission tomography (PET) imaging. More importantly, the application of large-pore MSN templates maintains the mesoporous structure of HMNPs, promising excellent drug loading capacity of these nanoparticles. As a proof-of-concept, HMNPs loaded with a high dose of DOX (chemotherapy agent) and Si-Pc (photosensitizer) are rationally designed for chemotherapy and NIR-PL-sensitized photodynamic therapy (PDT), respectively. Studies with mice tumor models demonstrate that the DOX/Si-Pc-loaded HMNPs possess excellent cancer cell killing ability and an outstanding tumor suppression effect without systemic toxicity. This work shows the great potential of HMNPs as an "all-in-one" nanotheranostic tool for multimodal NIR-PL/MR/PET imaging-guided chemotherapy and NIR-PL-sensitized photodynamic cancer therapy and provides an innovative paradigm for the development of NIR-PLNP-based nanoplatforms in cancer theranostic.

Large-Pore Mesoporous-Silica-Coated Upconversion Nanoparticles as Multifunctional Immunoadjuvants with Ultrahigh Photosensitizer and Antigen Loading Efficiency for Improved Cancer Photodynamic Immunotherapy.

Reported immunoadjuvants still have many limitations, such as inferior cellular uptake capacity and biocompatibility, overly large particle sizes, single function, and unsatisfactory therapeutic efficacy. Here, large-pore mesoporous-silica-coated upconversion nanoparticles (UCMSs) with a size of less than 100 nm are successfully prepared by a typical silica sol-gel reaction using mesitylene as a pore-swelling agent and are applied as a novel immunoadjuvant. The obtained UCMSs not only show significantly higher loadings for the photosensitizers merocyanine 540 (MC540), model proteins (chicken ovalbumin (OVA)), and tumor antigens (tumor cell fragment (TF)), but also are successfully employed for highly efficient in vivo vaccine delivery. The prepared UCMSs-MC540-OVA under 980 nm near-infrared irradiation shows the best synergistic immunopotentiation action, verified by the strongest Th1 and Th2 immune responses and the highest frequency of CD4+ , CD8+ , and effector-memory T cells. Additionally, nanovaccines UCMSs-MC540-TF can more effectively inhibit tumor growth and increase the survival of colon cancer (CT26)-tumor-bearing BALB/c mice compared with either photodynamic therapy or immunological therapy alone, suggesting the enhanced immunotherapy efficacy and clinical potential of UCMSs as immunoadjuvants for cancer immunotherapy.