Overcoming Drug Resistance in Multiple Myeloma: Targeting Bone Marrow with Nanoparticle-Mediated siRNA Delivery


Multiple myeloma (MM) is a challenging hematological malignancy characterized by relapse and short survival rates. Efforts to combat MM drug resistance have become an urgent clinical need.

In this context, a promising approach involves targeting the bone marrow microenvironment surrounding MM cells, aiming to impede MM homing, proliferation, and the development of drug resistance.

In this study, we present the development of a nanoparticle platform designed to overcome delivery barriers within the bone marrow and effectively deliver nucleic acid therapeutics.

Specifically, we demonstrate the efficacy of small interfering RNA (siRNA) silencing of cyclophilin A, a protein secreted by the bone marrow, to inhibit the spread of MM. Moreover, through a combination of our nanoparticle platform and the FDA-approved MM therapeutic bortezomib, we observed a remarkable extension in mouse survival compared to either treatment alone.

This siRNA nanotechnology holds significant potential as a versatile platform for treating other bone marrow-homing malignancies, offering new avenues for therapeutic interventions in cancer research.

siRNA molecules are short (usually 21 nucleotides long) double-stranded RNA (dsRNA) with two nucleotides protruding at each 3′ end. They are derived from longer precursors that are recognized and cleaved by an enzyme called Dicer . Dicer also processes another type of RNA molecules called microRNAs (miRNAs), which have similar functions but different origins and targets.

siRNA molecules can be introduced artificially into cells by various methods, such as transfection, electroporation, or viral vectors. The goal is to design siRNA molecules that are complementary to the mRNA sequence of the gene that we want to silence. Once inside the cell, siRNA molecules bind to a protein complex called RISC (RNA-induced silencing complex), which unwinds the dsRNA and selects one strand as the guide strand. The guide strand then pairs with the target mRNA and directs RISC to cleave it, preventing its translation into protein .

siRNA has become a powerful tool for studying gene function and validating drug targets in basic and applied research. By knocking down specific genes, we can observe the effects on cellular processes, pathways, and phenotypes. siRNA can also be used to inhibit the expression of genes that are involved in diseases, such as cancer, viral infections, or genetic disorders. For example, siRNA has been shown to suppress the replication of HIV , reduce tumor growth , and correct defective genes .

However, siRNA also faces some challenges and limitations for its use in research and medicine. One of them is the specificity of siRNA: how to ensure that siRNA only targets the intended gene and not other genes with similar sequences or off-target effects. This can be achieved by careful design and optimization of siRNA sequences, as well as by using methods to monitor and minimize off-target effects .

Another challenge is the delivery of siRNA: how to efficiently and safely deliver siRNA molecules to the cells and tissues of interest, without causing toxicity or immune responses. This can be achieved by using various carriers and delivery systems, such as nanoparticles, liposomes, polymers, or antibodies .

In this blog post, I will summarize the main findings of a recent paper published in PNAS by Guimarães et al. (2023), titled “In vivo bone marrow microenvironment siRNA delivery using lipid–polymer nanoparticles for multiple myeloma therapy”.

The paper reports a novel strategy to target the bone marrow microenvironment (BME) with siRNA-loaded nanoparticles for the treatment of multiple myeloma (MM), a type of blood cancer that affects plasma cells.

Multiple myeloma is a disease that originates from the clonal expansion of a single plasma cell in the bone marrow, which produces large amounts of an abnormal antibody called monoclonal protein (M protein). The M protein accumulates in the blood and tissues, causing various complications such as kidney damage, bone lesions, anemia, and infections.

Multiple myeloma is also characterized by the interaction between the malignant plasma cells and the surrounding BME, which provides support and protection for the tumor cells and contributes to drug resistance. Therefore, targeting both the tumor cells and the BME is essential for effective MM therapy.

One of the key components of the BME is a type of immune cell called macrophage, which can be either pro-inflammatory (M1) or anti-inflammatory (M2). In MM, the BME is enriched with M2 macrophages, which promote tumor growth, angiogenesis, and immunosuppression. Previous studies have shown that silencing a gene called STAT3 in M2 macrophages can reverse their phenotype to M1 and inhibit MM progression. However, delivering siRNA to M2 macrophages in vivo is challenging due to their low uptake efficiency and high degradation rate.

To overcome this obstacle, Guimarães et al. (2023) developed a novel type of nanoparticle that can efficiently deliver siRNA to M2 macrophages in the BME. The nanoparticle consists of a lipid-polymer hybrid core-shell structure that encapsulates siRNA molecules.

The lipid core provides stability and protection for the siRNA, while the polymer shell enhances the circulation time and biodistribution of the nanoparticle. The nanoparticle surface is also decorated with an antibody that specifically recognizes a receptor called CD206, which is highly expressed on M2 macrophages. This antibody enables the selective targeting and internalization of the nanoparticle by M2 macrophages in the BME.

The authors tested their nanoparticle system in a mouse model of MM, where human MM cells were injected into the bone marrow of immunocompromised mice. They found that their nanoparticles could effectively deliver STAT3 siRNA to M2 macrophages in the BME and reduce their expression of STAT3 and other M2-associated genes.

This resulted in a phenotypic switch of M2 macrophages to M1 and a decrease in their number and function. Moreover, they observed that their nanoparticle treatment could significantly inhibit MM tumor growth, reduce bone lesions, and prolong survival of the mice. They also demonstrated that their nanoparticle treatment could synergize with a conventional chemotherapeutic drug called bortezomib to enhance its anti-MM efficacy.

In conclusion, Guimarães et al. (2023) have developed a novel nanoparticle system that can selectively deliver siRNA to M2 macrophages in the BME and modulate their phenotype and function for MM therapy. Their study provides a proof-of-concept for targeting the BME with siRNA-loaded nanoparticles and opens new avenues for developing more effective and personalized treatments for MM patients.

reference link : https://www.pnas.org/doi/10.1073/pnas.2215711120


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