Synthetic bacteria as a targeted delivery system for small molecule therapeutics

Division Of Basic Sciences - Nci

Investigators

Abstract

In summary, we propose that SSHELs represent as a groundbreaking self-adjuvanting peptide delivery system. Their unique design allows them to mimic a natural presentation pathway for antigens, thereby eliciting a robust and targeted immune response. The ability of SSHELs to enhance peptide stability, improve cellular uptake and antigen presentation, and induce potent T cell expansion, all without the need for external adjuvants, positions them as a highly promising platform for the development of next-generation peptide-based immunotherapies. This innovative technology has the potential to revolutionize therapeutic immunization strategies, paving the way for more effective and safer treatments for a wide range of diseases. These achievements are expanded on below: Synthetic Spore-like Particles (SSHELs) for Enhanced Peptide-Based Immunotherapies Peptide-based therapeutics offer a promising avenue for medical applications such as cancer immunotherapy and infectious disease prevention by eliciting targeted T cell responses. However, their clinical utility has been limited by two significant challenges: poor immunogenicity and short in vivo stability. Free peptides often fail to adequately stimulate the immune system and are rapidly degraded by proteases and cleared from the bloodstream, leading to insufficient antigen presentation and diminished immune activation. To address these critical limitations, we developed and investigated "SSHELs" (Synthetic Spore-like HELs), previously reported as synthetic bacterial spore-like particles. Mechanism of Action: Overcoming Limitations with SSHELs Our studies demonstrate that SSHELs efficiently internalize peptide antigens into dendritic cells (DCs), which are crucial antigen-presenting cells for initiating T cell responses. Following internalization, SSHEL-delivered peptides are processed and cross-presented by DCs with remarkable efficiency, both in vitro and in vivo. This enhanced processing and cross-presentation, significantly superior to that observed with free peptides, indicates that SSHELs effectively protect peptides from degradation and facilitate their optimal delivery to the antigen presentation machinery within DCs. Optimizing T Cell Expansion: The Role of Particle Size and Presentation Mode Crucially, the enhanced antigen presentation orchestrated by SSHELs leads to robust antigen-specific T cell expansion. Our findings reveal that the effectiveness of this expansion is critically dependent on two key parameters: particle size and the mode of peptide presentation. We discovered that specific particle sizes elicit superior immune responses, suggesting an optimal size range for efficient cellular uptake and processing. Furthermore, our research highlighted that peptides encapsulated within the SSHEL structure were significantly superior in eliciting T cell responses compared to peptides merely attached to the particle's surface. This observation suggests that encapsulation provides better protection for the peptide and potentially facilitates its more efficient release and processing within the cell. Therapeutic Potential of SSHELs in a Melanoma Model To validate the therapeutic potential of SSHELs, we employed a well-established mouse melanoma model that expresses ovalbumin as a tumor-associated antigen. In this model, therapeutic immunization with SSHEL-delivered ovalbumin peptides led to significant and encouraging outcomes. We observed a notable reduction in tumor size and increased survival rates among the immunized mice, underscoring the therapeutic efficacy of SSHELs in a relevant disease setting and indicating an effective anti-tumor immune response.