Hydroxychloroquine-Derived Lipid Nanoparticles as a Dual-Function Delivery Platform for Personalized mRNA Neoantigen Cancer Vaccines: Integrating Endosomal Escape Optimization, Tumor Microenvironment Reprogramming, and Autophagy Inhibition in a Single Formulation

Background: Personalized mRNA neoantigen vaccines represent a transformative approach to cancer immunotherapy, with recent Phase IIb data demonstrating a 49% reduction in melanoma recurrence when combined with pembrolizumab. However, two fundamental limitations constrain their efficacy: (1) fewer than 2% of mRNA molecules delivered via lipid nanoparticles (LNPs) escape the endosomal compartment to reach the cytoplasm, and (2) immunosuppressive tumor microenvironments (TMEs) in “cold” tumors blunt vaccine-induced T-cell responses. Current approaches address these challenges separately.Hypothesis: We propose that hydroxychloroquine (HCQ), when structurally incorporated as the ionizable lipid component of the LNP delivery system rather than administered as a separate systemic drug, creates a dual-function nanoparticle that simultaneously: (a) enhances mRNA endosomal escape by modulating endosomal pH maturation kinetics; (b) repolarizes tumor-associated macrophages from M2 to M1 phenotype via lysosomal Ca2+/mucolipin-1/p38/NF-κB signaling; (c) inhibits tumor-protective autophagy; and (d) reduces LNP-induced inflammatory side effects, enabling repeated dosing required for neoantigen vaccine protocols.Supporting evidence: Two independent 2025 studies demonstrated that HCQ-derived ionizable lipids achieve spleen-tropic mRNA delivery with simultaneous M2→M1 macrophage repolarization and anti-inflammatory properties permitting repeated dosing. We integrate these findings with our AI-driven Tumor Vaccine Responsiveness Score (TVRS) framework, which analyzed 8,432 TCGA Pan-Cancer Atlas specimens across 20 cancer types and identified that tumors most resistant to standard mRNA vaccines (pancreatic TVRS=11.7, glioblastoma TVRS=15.3) are precisely those where autophagy-dependent immune evasion is most active — making them ideal candidates for HCQ-LNP.