Biocompatible And Low-Toxicity Lipid Nanoparticles (LNPs) For Selectively Delivering mRNA To The Bone Microenvironment

Ionizable LNPs with a rigid backbone of piperazine (PIP) linked to bisphosphonates (BPs) for the targeted delivery of mRNA to the bone.
Problem:
Available treatments for bone tissue related diseases provide only symptomatic relief and are associated with clinical challenges and potential side effects. Challenges persist in the delivery of therapeutic agents to the bone microenvironment characterized by low blood flow and dense cortical structure, leading to limited interaction between bone and blood. Consequently, issues such as poor delivery efficiency and long-term bioavailability constraints arise. Conventional approaches often involve the use of excessive therapeutic agents, which may lead to secondary effects such as intestinal inflammation and ulcers. Current bone targeted LNPs have adverse effects like gastrointestinal issues and decreased blood supply to bones.
Solution:
The developed bone-targeted LNPs enable targeted and localized interactions with cells distributed within a bone, facilitating the role of gene therapy in the cellular signaling pathways of diseases such as osteosarcoma. The bone-targeting ionizable lipids demonstrated high cell viability and strong binding affinity with bone constituents.

Technology:
The developed ionizable LNPs use a PIP backbone functionalized with BPs such as AlendronateTM for bone-targeted mRNA delivery systems. A PIP structure with a chair-form configuration was introduced to immobilize the movement of BP molecules. The PIP ring undergoes amide bond formation with acyl groups via coupling reactions to form bone-targeting ionizable lipids. Additionally, these formed amides play a vital role in enhancing mRNA expression by assisting in the late stage of endosomal escape. Diverse synthesis designs of bone-targeting ionizable lipids were developed chemically to facilitate lysosomal-endosomal escape that is required to induce mRNA expression.

Advantages:

Low toxicity in cells and exceptional biocompatibility
Successful in vivo delivery of mRNA through LNPs targeting only bone cells
The PIP backbone facilitated targeted and localized bone delivery while minimizing adverse effects
PIP and BPs were used to develop ionizable lipids to enhance binding affinity to bone tissue and reduce side-effects caused by off-target mRNA delivery
Large molecular weight ionizable lipids are used to enhance the stability of the resulting bone-targeted LNPs and to produce LNPs with a uniform size distribution

Stage of Development:

Preclinical Discovery

(A) Illustration of systematic delivery of piperazine-based bisphosphonate-linked ionizable lipids to the bone microenvironment.
Intellectual Property: