Regulation of cerebral blood flow boosts precise brain targeting of vinpocetine-derived ionizable-lipidoid nanoparticles.

Despite advances in active drug targeting for blood-brain barrier penetration, two key challenges persist: first, attachment of a targeting ligand to the drug or drug carrier does not enhance its brain biodistribution; and second, many brain diseases are intricately linked to microcirculation disorders that significantly impede drug accumulation within brain lesions even after they cross the barrier. Inspired by the neuroprotective properties of vinpocetine, which regulates cerebral blood flow, we propose a molecular library design centered on this class of cyclic tertiary amine compounds and develop a self-enhanced brain-targeted nucleic acid delivery system. Our findings reveal that: (i) vinpocetine-derived ionizable-lipidoid nanoparticles efficiently breach the blood-brain barrier; (ii) they have high gene-loading capacity, facilitating endosomal escape and intracellular transport; (iii) their administration is safe with minimal immunogenicity even with prolonged use; and (iv) they have potent pharmacologic brain-protective activity and may synergize with treatments for brain disorders as demonstrated in male APP/PS1 mice.

Breaking Spatiotemporal Barriers of Immunogenic Chemotherapy via an Endoplasmic Reticulum Membrane-Assisted Liposomal Drug Delivery.

Immunogenic chemotherapy is a promising approach in cancer treatment, but the number of drugs capable of inducing immunogenic cell death is limited, and chronic immunogenic exposure can delay antitumor immune response and be counteracted by immunosuppressive factors. In this study, we used single-cell and multilevel analyses to highlight the critical importance of the first exposure to calreticulin (CRT) in eliciting immunogenicity. We then developed the ERASION (endoplasmic reticulum (ER) membrane to assist (AS) the presentation of intrinsic onco-immunogenicity (ION)) strategy, leveraging the high expression of functional proteins, including CRT, on the ER membrane. ER membrane-coated liposome (ER@PLip) was able to target the tumor and immune effectors and promoted dendritic cell maturation and T cell infiltration. This enabled eliciting an immunogenic effect from a nonimmunogenic chemotherapeutic drug. By utilizing the ER membrane-associated STING protein, ERASION enabled activating the STING pathway and the generation of adaptive antitumor immunity. This study presents a potential universal platform for integrating traditional chemotherapy and therapeutic modalities.