Biomimetic radiosensitizers unlock radiogenetics for local interstitial radiotherapy to activate systematic immune responses and resist tumor metastasis

Abstract

Background Similar to other local therapeutic methods, local interstitial radiotherapy (IRT) also suffers from insufficient systematic immune activation, resulting in tumor metastasis. Results Mn-based IRT radiosensitizers consisting of 131I, MnO2 and bovine serum albumin (BSA) (131I-MnO2-BSA) were engineered. Such Mn-based IRT radiosensitizers successfully unlocked radiogenetics to magnify systematic immune responses of local IRT via remodeling hypoxic and immunosuppressive microenvironments and resist tumor metastasis. The MnO2 in 131I-MnO2-BSA caused decomposition of H2O2 enriched in tumors to generate O2 for alleviating hypoxic microenvironment and removing tumor resistances to IRT. Concurrently, hypoxia mitigation by such radiosensitizers-unlocked radiogenetics can effectively remodel immunosuppressive microenvironment associated with regulatory T (Treg) cells and tumor-associated macrophages (TAMs) infiltration inhibition to induce immunogenic cell death (ICD), which, along with hypoxia mitigation, activates systematic immune responses. More intriguingly, 131I-MnO2-BSA-enabled radiogenetics can upregulate PD-L1 expression, which allows anti-PD-L1-combined therapy to exert a robust antitumor effect on primary tumors and elicit memory effects to suppress metastatic tumors in both tumor models (4T1 and CT26). Conclusions IRT radiosensitizer-unlocked radiogenetics and the corresponding design principle provide a general pathway to address the insufficient systematic immune responses of local IRT. Graphical Abstract

Nanomaterials-Based Tumor Microenvironment Modulation for Magnifying Sonodynamic Therapy

“…In addition, Mn-based nanosystems also share the identical actions after rational engineering, such as hollow manganese dioxide (HMnO 2 ) nanostructures. 9,29,30,40 Our group also did an innovative job where combining HMnO 2 with tyrosinasetriggered oxidative stress amplifier (APAP) was implemented. 29 HMnO 2 could react with intratumoral H 2 O 2 to release O 2 to reverse tumor hypoxia and enhance ROS production (Figure 3h) and also boost GSH consumption to attain redox homeostasis disruption and amplify oxidative stress for resisting tumor growth (Figure 3i).…”

“…We also used Mn-based nanoparticles to reach CDT and O 2 release for removing hypoxia-induced resistance to radiotherapy and strengthening radiotherapy-activated immunotherapy (Figure 4b). 40 Besides the above inorganic transition metal based nanoenzymes, catalase could also decompose endogenous H 2 O 2 into O 2 to alleviate hypoxic TME, 22,42 19,42 where the TCM entrapment allowed Fe-PDAP to keep silent under physiological conditions and minimize the undesired H 2 O 2 consumption in TME. Upon exposure to US stimulus for dismantling TCM, the naked Fe-PDAP restored its catalytic activity and promoted H 2 O 2 breakdown to produce O 2 for mitigating hypoxia and enhancing Ce6-mediated sonocatalytic ROS production, which could unite with immune checkpoint blockade (ICB) therapy to prevent primary and metastatic tumors via activating systematic immune responses (Figure 4c).…”

“…More significantly, GSH was significantly depleted, further promoting ROS production for enhancing SDT efficacy in osteosarcoma treatment (Figure a–d), and this nanoplatform successfully makes the net level of ROS rise more via breaking the redox balance to GSH drop and simultaneously triggering SDT and CDT to boost ROS birth (Figure e–g). In addition, Mn-based nanosystems also share the identical actions after rational engineering, such as hollow manganese dioxide (HMnO 2 ) nanostructures. ,,, Our group also did an innovative job where combining HMnO 2 with tyrosinase-triggered oxidative stress amplifier (APAP) was implemented . HMnO 2 could react with intratumoral H 2 O 2 to release O 2 to reverse tumor hypoxia and enhance ROS production (Figure h) and also boost GSH consumption to attain redox homeostasis disruption and amplify oxidative stress for resisting tumor growth (Figure i).…”

“…Regarding this, increased O 2 supply to ameliorate oxygen deprivation or even reverse hypoxia is essential and highly deserves the expectation in elevating the ROS production efficiency in SDT, PDT, CDT, etc. − Great advances in designing and constructing pathways to provide adequate O 2 have been witnessed to boost SDT, e.g. , endogenous or exogenous stimuli activated in situ O 2 birth and exogenous-propelled O 2 delivery.…”

Emerging nanobiotechnology-encoded relaxation tuning establishes new MRI modes to localize, monitor and predict diseases

“…Due to the high spatial resolution, inherent soft-tissue contrast and ion-free radiation, MRI is a promising visualization tool that has been utilized to qualitatively track large numbers of cells in vivo , 134 among which immune effector cells and immunosuppressive cells are highlighted because their distribution and infiltration directly decide the success or failure of anti-tumor immunotherapy. 135–137 Luo et al developed a bioactivated in vivo assembly method and synthesized a CD206-targeting molecular MRI probe with cathepsin B-sensitive linker. As the probe entered macrophages, the intracellular cathepsin B degraded the linker and induced the probe to assemble into nanofibers with enhanced T 1-weighted MRI, which allowed the real-time tracking of macrophage migration (Fig.…”