Systemic Delivery Strategies for Oncolytic Viruses: Advancing Targeted and Efficient Tumor Therapy

Abstract

The rapid development of therapies using oncolytic viruses (OVs) has highlighted their unique advantages, such as their selective replication in tumor cells and their activation of a specific systemic antitumor immune response. However, effectively delivering OVs to tumor sites, especially solid tumor sites, remains a critical challenge. Intratumoral injections face significant barriers in treating some malignant tumors in internal organs, while increasing preclinical data support the use of intravenous injections. Nevertheless, intravenously injected viral particles may be prematurely cleared by circulating antibodies or complements, resulting in a reduced virus dose effectively reaching the tumor site. Therefore, developing methods to shield viruses from the neutralizing environment of the bloodstream while heading toward tumor sites is a must. In this review, we discuss some of the most promising delivery methods for OVs currently under investigation.

Keywords: delivery methods; intravenous injection; oncolytic virus.

Figure 1

Several effective delivery strategies for OVs, including cell carriers, binding with proteins and nanoparticle (NP) carriers. (1) Cell carriers: utilizing the intrinsic tumor-homing capacity of cellular carriers, including inactivating tumor cells, monocytes/macrophages, T cells and MSCs, to deliver OVs to tumor tissues. Following targeted delivery, OVs infect and lyse tumor cells, releasing progeny viruses; (2) Binding with proteins: the virus-protein corona replacement strategy forms an artificial protein corona on OVs to prevent neutralization by antibodies and complement, while suppressing natural corona formation; The modification of key capsid proteins strategy introduces mutations on the viral capsid surface to evade recognition in the bloodstream; (3) NPs carriers: NPs deliver OVs through active targeting mechanisms. Active delivery means specifically binding and directing the movement of nanoparticles to the target tumor tissue inside the body, including antibodies, PEG chains, polysaccharides, aptamers, peptides, and small molecules with a strong affinity and specificity for receptors and excessive molecules on tumor cells.

Figure 2

Tumor-homing mechanisms of cell carriers. (A) The homing and retention capacity of tumor cells are associated with the expression of CXCR4 and CD44 on the cell membrane; (B) Macrophages can specifically recognize VCAM-1 via α4β1 integrin, enabling targeted homing to tumor tissues. Additionally, tumor-secreted CCL2 and CCL5 recruit macrophages into the TME; (C) Tumor-secreted chemokines recognize GPCRs on T-cell surfaces and trigger downstream signaling pathways, facilitating the migration of T lymphocytes to the tumor site; (D) The molecular mechanism of MSCs homing involves five key steps: (1) Chemokine-receptor interaction; (2) Adhesion molecule-mediated anchoring; (3) Extravasation; (4) Transendothelial migration; (5) Interstitial migration.

Figure 3

Preparation of binding with protein carriers. Protein corona formation and modification of key capsid proteins.

Figure 4

Preparation of NPs carriers. (A) The surfaces of OVs were encapsulated by NP layers to retain the activation of OVs during systemic circulation. The “microbial-OV conjugate” was then constructed by combining tumor-homing microbial with NP-OA through a biocondensation reaction, named microbial NPs-OVs; (B) OA carries a negative charge at physiological pH because of carboxyl-rich anionic peptides on its surface. Adding MnCl2 and CuCl2 causes Mn²⁺ and Cu²⁺ to adsorb onto OA. Subsequent sodium carbonate addition under physiological conditions stops ion polymerization, spontaneously forming a moderately thick mineral shell around OA; (C) Preparation of BCMNs@OA.