The innate immune system is implicated in an enormous number of processes such as malignancy, inflammation, and tissue regeneration that affect millions of people worldwide. Developing new approaches to program innate immunity has important clinical and research applications such as enhancing current T-cell-based immunotherapeutic approaches by inducing a multilayered immune response; improving disease diagnosis and prognosis; and advancing the current understanding of immune activities in cancer, inflammation, and tissue regeneration. Precise targeting of innate immunity is still a challenge, as therapies can often be a double-edged sword and cause either systemic immune suppression or serious autoimmune/non-specific inflammation.
Dendrimer-based Nanoplatform for mRNA Delivery
Around 85% of proteins produced in the human body cannot be modulated by conventional therapeutic small molecules and antibodies. mRNA-based therapeutics have the potential to address such ‘undruggable’ targets. The current lipid nanoparticle-based mRNA delivery platforms intrinsically deliver mRNA cargos to the liver, spleen, and lung. However, to address diseases in hard-to-deliver tissues such as the brain, we need to develop more diverse mRNA delivery systems that target various tissues. Our lab explores dendrimer, a type of polymer with ‘tree-like’ branched architecture, as a unique mRNA delivery material. As a unique molecule, dendrimer possesses a high degree of molecular uniformity as small molecules and the broad theoretical space for chemical tuning as polydisperse polymers. Our lab seeks to establish a fundamental understanding of how dendrimer chemical structure, such as their generations and surface properties, affect their intracellular fate and in vivo biodistribution. Check out some of our related studies below.
PbAE-based mRNA delivery platform: mRNA is formulated with a cationic polymer called Poly-beta aminoester (PbAE) to form a polyplex through electronstatic interaction.
The chemical structure of PAMAM dendrimer: a type of polymer with ‘tree-like’ branched architecture. The high density of termial functional groups and the flexible structure of this material provide potential for mRNA delivery.
Genetically Program Macrophage Function
As key players in innate immunity, macrophages constitute 5-20% of the cells in major tissues of the body. In cancer, macrophages infiltrate into the tumor in large numbers during the process of cancer development. Numerous clinical studies have indicated a strong association between the suppressive macrophage population and poor prognosis in multiple common cancer types. Given the large population of tumor-associated macrophages and the key roles these cells play in cancer, macrophages are unique cellular targets for cancer immunotherapy, which currently focuses on T cells. Our group seeks to use nanoplatforms to engineer macrophages as ‘living therapeutics’, through genetically programming cellular functions or molecularly targeting stimulatory/inhibitory pathways. Check out some of our related studies below.
Genetically program macrophage with different immune functionalities.
The immune-suppressive tumor-associated macrophage can be reprogramed to an immune-stimulatory phenotype, which further leads to tumor elimination.
Physiology-guided Cancer Delivery
The successful clinical translation of nanomedicine requires an integration of the pathophysiology into drug delivery design. In cancer, the stage of malignancy affects the heterogeneous tumor microenvironment, such as the tumor-infiltration lymphocytes composition, phenotype, infiltration kinetics; the pore size of the tumor vasculature; and the density of the extracellular matrix, etc. The dynamics of these properties need to be integrated with the designing of a drug delivery platform, for example, the size, charge, surface properties, and structural flexibility. In addition, physiology also plays an important role in determining the fate of the drug delivery platforms in vivo. For example, the pharmacokinetics of nanoparticles is affected by a combined effect of the renal clearance system, the mononuclear phagocyte system, and the hepatic clearance system. Our lab seeks to use nanoparticles as a probe to understand the dynamic change of pathophysiology in the context of solid tumors and to integrate this with pharmacokinetics modeling. The information gathered from these studies will then be used to guide the design and clinical translation of nanotherapeutics. Check out some of our related studies below.
With the appropriate physiochemical properties, nanoparticles can efficiently cross the impaired blood-brain tumor barrier (within 15 min), uniformly distributed throughout the tumor, and uptake by activated macrophage in brain tumors (within 4 hours).
Nanoparticles’ sizes affect their in vivo fate. When increasing the dendrimer generation from G4 to G6 (equivalent to the size increase from 4.3nm to 6.7nm), the circulation period of nanoparticles also extended significantly.