Abstract Introduction: Immunotherapy efficacy in solid tumors is often limited by immune tolerance within tumor-draining lymph nodes (TDLNs), where antigen presentation and T-cell priming originate. Immune activators, such as STING agonists, are capable of reversing local immunosuppression, however their clinical translation has been hindered by rapid systemic clearance, dose-limiting toxicity, and poor lymph node bioavailability. Effective targeting of TDLNs could overcome these translational barriers by reprogramming local immune environments and amplifying durable antitumor immunity. To address this, we have developed a novel delivery platform T-Lymphocyte Mimetic Membrane-wrapped Microparticles (T3MPs). Methods: T3MPs were fabricated using a flow-focusing microfluidic device to generate uniform, cell-sized alginate microparticles (10-20 µm). Multiple payloads, including cyclic-di-GMP (STING agonist) and cisplatin, were encapsulated within the alginate matrix during particle formation. Drug-loaded T3MPs were cloaked with allogenic T-cell membranes to preserve trafficking proteins, confirmed via flow cytometry. Drug encapsulation and release kinetics were quantified via spectrofluorometry. In vitro payload functionality was assessed with THP-1 culture, and in vivo biodistribution and efficacy were evaluated following intravenous administration in BALB/c mice. Results: T3MPs exhibited uniform size distribution and retained key lymphocyte surface proteins (L-selectin, LFA-1) critical for LN trafficking and demonstrated tunable, sustained drug release, achieving ∼50% release over 10 days in vitro. Following intravenous administration, drug-loaded T3MPs achieved ∼700% greater LN-specific delivery than free drug controls and extended the therapeutic index 500-fold by reducing systemic exposure. Delivery of c-di-GMP via T3MPs induced potent activation of lymph node resident antigen presenting cells (elevated IFN-β and IL-12), while co-delivery of c-di-GMP and model tumor antigen (SIINFEKL) enhanced antigen-specific CD8+ T-cell priming. Conclusions: T3MPs represent a novel lymphocyte-mimetic platform that overcomes pharmacological barriers to lymph node drug delivery, enabling safe, localized immunomodulation for reprogramming immune niches. By combining lymphocyte-inspired targeting with tunable release, this technology offers a broadly applicable strategy to enhance the efficacy of immunotherapies and vaccines. Ongoing work through Navicyte Biotechnologies is advancing the T3MP platform toward IND-enabling studies and strategic pharmaceutical partnerships. Citation Format: Michael J. Donzanti, Luisa A. Fink, Bahar Bahramimeimandi, Kayla Katz, Dylan T. Ngo, Ana Obradovic, Ryan Zurakowski, Jason P. Gleghorn. Lymphocyte-mimetic drug carriers enable targeted therapeutic delivery to lymph nodes for enhanced immunomodulation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3020.
Donzanti et al. (Fri,) studied this question.