Activation of the innate immune STimulator of INterferon Genes (STING) pathway potentiates antitumour immunity, but systemic delivery of STING agonists to tumours is challenging. We conjugated STING-activating cyclic dinucleotides (CDNs) to PEGylated lipids (CDN-PEG-lipids; PEG, polyethylene glycol) via a cleavable linker and incorporated them into lipid nanodiscs (LNDs), which are discoid nanoparticles formed by self-assembly. Compared to state-of-the-art liposomes, intravenously administered LNDs carrying CDN-PEG-lipid (LND-CDNs) exhibited more efficient penetration of tumours, exposing the majority of tumour cells to STING agonist. A single dose of LND-CDNs induced rejection of established tumours, coincident with immune memory against tumour rechallenge. Although CDNs were not directly tumoricidal, LND-CDN uptake by cancer cells correlated with robust T-cell activation by promoting CDN and tumour antigen co-localization in dendritic cells. LNDs thus appear promising as a vehicle for robust delivery of compounds throughout solid tumours, which can be exploited for enhanced immunotherapy.
Nanoparticle modification with poly(ethylene
glycol) (PEG) is a
widely used surface engineering strategy in nanomedicine. However,
since the artificial PEG polymer may adversely impact nanomedicine
safety and efficacy, alternative surface modifications are needed.
Here, we explored the “self” polysaccharide heparosan
(HEP) to prepare colloidally stable HEP-coated nanoparticles, including
gold and silver nanoparticles and liposomes. We found that the HEP-coating
reduced the nanoparticle protein corona formation as efficiently as
PEG coatings upon serum incubation. Liquid chromatography–mass
spectrometry revealed the protein corona profiles. Heparosan-coated
nanoparticles exhibited up to 230-fold higher uptake in certain innate
immune cells, but not in other tested cell types, than PEGylated nanoparticles.
No noticeable cytotoxicity was observed. Serum proteins did not mediate
the high cell uptake of HEP-coated nanoparticles. Our work suggests
that HEP polymers may be an effective surface modification technology
for nanomedicines to safely and efficiently target certain innate
immune cells.
Tissue-resident memory T cells (TRMs) can profoundly enhance mucosal immunity, but parameters governing TRM induction by vaccination remain poorly understood. Here, we describe an approach exploiting natural albumin transport across the airway epithelium to enhance mucosal TRM generation by vaccination. Pulmonary immunization with albumin-binding amphiphile conjugates of peptide antigens and CpG adjuvant (amph-vaccines) increased vaccine accumulation in the lung and mediastinal lymph nodes (MLNs). Amph-vaccines prolonged antigen presentation in MLNs over 2 weeks, leading to 25-fold increased lung-resident T cell responses over traditional immunization and enhanced protection from viral or tumor challenge. Mimicking such prolonged exposure through repeated administration of soluble vaccine revealed that persistence of both antigen and adjuvant was critical for optimal TRM induction, mediated through T cell priming in MLNs after prime, and directly in the lung tissue after boost. Thus, vaccine persistence strongly promotes TRM induction, and amph-conjugates may provide a practical approach to achieve such kinetics in mucosal vaccines.
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