Smart Nanoparticles Advance Use of Nucleic Acid Technology in Cancer Immunotherapy


Recent developments in nanoparticle-mediated cancer immunotherapy promote treatment with less toxicity.

Advanced smart nanoparticles enhance the delivery of nucleic acid therapeutics to cancer cells, addressing many of the barriers that have hindered their clinical applications, according to a review published in Pharmaceutics.

Cancer immunotherapy utilizes a patient’s immune system to target and destroy cancer. Many types of nucleic acids can modify the expression of genes or serve as agonists for activating innate immune response pathways, thereby modulating the immune response to cancer.

A major opportunity remains for the development of therapeutic nucleic acid for cancer immunotherapy in the forms of cancer vaccines, adoptive T-cell therapies, and regulation, the authors wrote. However, these technologies face many challenges, including in vivo decay, limited uptake by target cells, requirements for nuclear penetration (in some cases), and damage caused to healthy cells.

“These barriers can be avoided and resolved by utilizing advanced smart nanocarriers that enable the efficient and selective delivery of nucleic acids to the target cells and tissues,” they said. “Nucleic acid molecules are shielded by nanoparticle delivery systems.”

In their review, the authors summarized recent studies on nanoparticle-mediated cancer immunotherapy. They presented the characteristics of different types of nanoparticles and the crosstalk between the function of nucleic acid therapeutics in cancer immunotherapy.

In contrast to other delivery systems, the versatility and the unique properties of nanoparticles (magnetic, optical, chemical, and structural) offer numerous advantages. Notably, their properties can be engineered to obtain specific surface chemistries, sizes, physical properties, and material compositions. Each material offers distinctive delivery advantages.

The authors also detailed key advantages and disadvantages of numerous nanoparticles, characterized into 2 types: chemically and biologically synthesized. The following summary highlights basics from current literature on advanced smart nanocarriers: 

  • Lipid-based nanoparticles offer low toxicity, high loading capacity, and controlled release:
    • Numerous liposomal nanoparticles have been developed for site-targeted delivery with a low toxicity and a high loading capacity
    • They are the most advanced platform because they are the least toxic
    • Their properties and performance can be controlled by changes in the ratio of lipid constituents, surface chemistry, and synthesis methods
    • Advantages include formulation simplicity, high bioavailability, and payload flexibility
    • Low encapsulation efficiency is a disadvantage
  • Inorganic nanoparticles have been shown to offer great efficiency and reproducibility for cancer vaccination techniques:
    • They deliver tumor antigens and immune adjuvants to targeted sites due to their compliant surface chemistry and customizable shape
    • Of all the inorganic nanoparticles, gold nanoparticles (AuNPs) have undergone extensive research and together they are well established as a system to deliver tumor antigens and immune adjuvants
    • They have distinctive optical features that can be used for controlled tumor ablation; other advantages include their unique electrical and magnetic properties
    • Disadvantages include toxicity and solubility limitations
    • AuNPS can accumulate in organs over time, thus constituting a safety concern
  • Polymer-mediated nanoparticles can act as both adjuvants and delivery vehicles for immune-stimulating compounds when immune responses are stimulated to hinder the growth rate of tumors; they are widely used as adjuvants due to superior biocompatibility and solubility
  • Hybrid nanoparticles contain inorganic and organic components to take advantage of both to enhance biocompatibility and efficiency, and to reduce toxicity
  • Spherical nucleic acids (SNAs), another class of smart nanoparticles, are nanostructures consisting of nucleic acids that are densely functionalized:
    • SNAs offer a different approach for gene and medication delivery
    • Although inorganic nanoparticles are most frequently used to make SNAs, their propensity to concentrate in organs—such as the liver and spleen—poses possible long-term health implications
    • Recent developments have accelerated their potential for clinical use 

To summarize, nucleic acid–mediated immunotherapy has demonstrated efficiency in cancer treatment. Different types of nucleic acids—such as messenger RNA, small interfering RNA, micro RNA, aptamer, and plasmid—can be used to modulate antitumor immunity.

Despite the success of nanoparticle-mediated approaches in numerous preclinical research and clinical situations, many obstacles remain. Some elements in nanoparticles may irritate the skin, produce inflammation, and trigger the body’s defense mechanisms. Further, their limited circulation duration and potential cytotoxicity require careful consideration.

Still, recent advancements in modification techniques make nanoparticles an excellent and mature nucleic acid delivery technology, the author concluded.

“Nanoparticle-based nucleic acid delivery platforms will become more promising and advanced in upcoming clinical applications as the understanding of nanoparticles for nucleic acid delivery is strengthened,” they said.


Baker A, Lorch J, VanderWeele D, Zhang B. Smart nanocarriers for the targeted delivery of therapeutic nucleic acid for cancer immunotherapy. Pharmaceutics. 2023;15(6):1743. doi:10.3390/pharmaceutics15061743

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