Innate immune system is an important arm of host immune defense mechanisms that produces a non-specific rapid response to pathogens or other hazardous factors, and plays a role in resisting the invasion of pathogens and clearing senescent and cancerous cells.

Recently, Chair of SAHZU Orthopedics Prof. YE Zhaoming and his team have published two research articles in Advanced Materials regarding the critical role of innate immune system in bone infection and osteosarcoma.

Novel antibacterial strategy based on the regulation of autogenous immunity: the role of infection-associated macrophages

Deep tissue infection is a common clinical issue and therapeutic difficulty caused by the disruption of the host antibacterial immune function, resulting in treatment failure and infection relapse. In such case, therapeutic options are often limited and rely heavily on aggressive antibiotic chemotherapy, which may further cause substantial harm to host immune function and often yield unsatisfactory therapeutic outcomes. In view of this, the pursuit of novel approaches to combat infections holds paramount importance.

Upon infection, innate immunity is immediately activated to eliminate invasive pathogens. However, invasive pathogens, such as Staphylococcus aureus, have evolved sophisticated mechanisms to evade antibacterial strategies. They are able to hide inside the host cells and can manipulate their biology even after appropriate treatment, resulting in a locoregional immunosuppressive state that leads to an inadequate response to conventional anti-infective therapies.

An innovative strategy to harness host immune responses for the treatment of deep tissue infections was presented by Prof. YE and his team in their article titled “An On-Demand Collaborative Innate-Adaptive Immune Response to Infection Treatment” published in Advanced Materials on July 31.

Figure 1. Schematic illustration of the reversal of immunosuppressive infectious microenvironment by nanoparticle-armed infection-associated macrophages (IAMs), achieving infection treatment and preventing relapse via autogenous immunity remodeling.

Macrophages, as essential components of the innate immune system, are monocyte-derived cells that form a bridge with the adaptive immune arm and regulate host immune homeostasis. They recognize and perform sequential engulfment of bacteria, and process antigen presentation to the adaptive immune cells after intracellular destruction of pathogens in the presence of the reactive oxygen species (ROS).

The research team found that inadequate ROS levels in infected macrophages led to intracellular survival of invading pathogens, skewing the macrophage response from the pro-inflammatory M1 phenotype towards an anti-inflammatory M2 phenotype. Resembling those of tumor-associated macrophages (TAMs) that play pivotal roles in the formation of the complex tumor immunosuppressive microenvironment, the compromised infected macrophages would cause a similar critical failure in priming of adaptive immunity, subsequently leading to immune exhaustion and infection development.

Based on the intrinsic antibacterial process of macrophages, the researchers aimed to utilize the metabolic alterations occurring in macrophages infiltrating infection sites and described an artificially inducible collaborative innate-adaptive immune response for immune recovery and precise infection treatment. Thus, they constructed a regulatory system (MφL@BSA@Man-ICG NPs) for on-demand collaborative innate-adaptive immune responses for infection treatment.

Specifically, a pH-responsive hybrid membrane shell (MφL) by integrating the murine macrophage line J774.1A membranes and pH-responsive vesicles, which were then encapsulated with the functional core BSA@Man-ICG to obtain biomimetic nanoclusters.

An instant ROS burst within nanoparticle-armed macrophages induced via in-situ photodynamic therapy eliminated residual pathogens. Additionally, ROS can activate the NF-κB signaling axis, which promotes macrophage M1 repolarization and initiates macrophage-central antibacterial immune responses. Moreover, they observed enhanced antigen presentation and T-cell priming by in-situ armed macrophages, which resulted in highly activated production of inflammatory factors to reinforce a robust collaborative innate-adaptive antibacterial immunity.

This study demonstrated the crucial role of IAMs in host defense against bacterial infections. IAM-directed host innate adaptive immune responses, based on ROS generation by intracellular BSA@Man-ICG, achieved S. aureus clearance and prevented bacterial relapse. Nanoparticle-armed macrophages, reminiscent of CAR-M cells, represent a simple cell-engineering strategy. It solves the ROS regulation problem that leads to intracellular bacterial survival and cellular compromise and consolidates the vital role of infectious immune microenvironment remodeling in bacterial infection treatment.

KERS-inspired nanostructured mineral coatings boost IFNγ mRNA therapeutic index for antitumor immunotherapy

Tumor-associated macrophage (TAM) reprogramming is a promising therapeutic approach for cancer immunotherapy; however, its efficacy remains modest due to the low bioactivity of the recombinant cytokines used for TAM reprogramming.

mRNA therapeutics are capable of generating fully functional proteins for various therapeutic purposes but accused for its poor sustainability. Therefore, improving the sustainability of mRNA delivery is important for the development of effective mRNA-based therapeutics.

Inspired by Kinetic Energy Recovery Systems (KERS), a power control system that improves fuel efficacy by storing energy during braking and subsequently releasing recycled kinetic energy for acceleration in hybrid vehicles, SAHZU researchers pioneered the Cytokine Efficacy Recovery System (CERS) to substantially augment the therapeutic index of mRNA-based agents, not only by improving the mRNA expression, but also by recycling the expressed cytokines via an energy recovery system for hybrid cars.

Figure 2. (Upper left) Schematic illustration of KERS, which is to make full use of kinetic energy by recovery. (Upper right) Schematic illustration of CERS, mimicking the KERS for fully exploit cytokine efficacy: ① the mRNA enters effector cells through LNPs and translates into cytokines, and soluble mineral ions (such as Ca2+) from MCMs and surface modification of LNPs increase mRNA delivery efficiency; ② a part of cytokines stimulates target cells through receptors, and another part of unworked cytokines is captured by MCMs in CERS and stabilized against denaturation by the nanostructured mineral coatings; ③ cytokines are re-released and stimulate target cells as nanostructured mineral coatings gradually dissolves in the slightly acidic environment of the tumor. (Bottom) CERS-mediated IFNγ chemically modified RNA (cmRNA) delivery expresses with high bioactivity and long duration, which effectively activates effector cells, thereby inhibiting tumor cell proliferation and activating immune responses.

This study was a collaborative research work of Prof. YE, SAHZU Orthopedic Surgeon Prof. YU Xiaohua, and Prof. CUI Wenguo from Ruijin Hospital of Shanghai Jiao Tong University School of Medicine. Their article titled KERS-inspired Nanostructured Mineral Coatings Boost IFNγ Mrna Therapeutic Index for Antitumor Immunotherapy was published in Advanced Materials on August 16.

The research team employs mineral-coated microparticles (MCMs) as mRNA delivery vehicles in CERS, as MCMs were previously reported to be able to both effectively improve transgene expression via secreted mineral ions and capture expressed protein in situ via nanostructured mineral coating. In response to the slightly acidic environment of the tumor, the MCMs then re-release the captured cytokines to extend the therapeutic window of the cytokines. Liposome nanoparticles (LNPs) of CERS are also modified to increase the mRNA delivery precision, as the surface-modified LNPs readily bind to target cells (Scheme 1C).

Based on the above-mentioned efforts, the KERS-inspired CERS is hypothesized to drive more efficient mRNA-based production of therapeutic cytokines with the active capture and stabilization of labile cytokines, thereby greatly improving the efficacy and reducing the cost and side effects of cytokine therapy.

Using IFNγ as an example, it is demonstrated that CERS-mediated mRNA therapy induced a nearly 40% increase in translation efficiency and captured ~40% of labile IFNγ proteins, resulting in the doubling of IFNγ activity time. Compared with commercial rIFNγ, IFNγ expressed by mRNA@CERS exhibits ~42-fold higher biological activity. When used for immunotherapy for osteosarcoma, CERS-mediated IFNγ mRNA delivery effectively reprogramed tumor-associated macrophages (TAMs) into tumoricidal macrophages and substantially inhibited tumor growth by inducing antitumor immunity. Interestingly, extremely malignant lung metastases even magically disappeared after receiving CERS-mediated IFNγ mRNA delivery combined with programmed cell death ligand-1 (PD-L1) antibody treatment (Scheme 1D).

Overall, inspired by KERS concept of hybrid electrical vehicles, CERS-mediated mRNA therapy via recovering cytokine efficacy provides a novel approach for efficient and sustained cytokines biotherapy, suitable for a wide range of medical applications.

Source: The Second Affiliated Hospital Zhejiang University School of Medicine (SAHZU)