Cover Page The handle

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Cover Page

The handle http://hdl.handle.net/1887/136519 holds various files of this Leiden University

dissertation.

Author: Benne, N.

Title: Vaccination and targeted therapy using liposomes : opportunities for treatment of

atherosclerosis and cancer

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ϳ

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dŚĞ ŝŵŵƵŶĞ ƐǇƐƚĞŵ ŝƐ ŽƵƌ ďŽĚǇ͛Ɛ ĚĞĨĞŶƐĞ ĂŐĂŝŶƐƚ ŝŶĨĞĐƟŽŶƐ͘ ,ŽǁĞǀĞƌ͕ ŝƚ ĐĂŶ also be involved in diseases such as autoimmune diseases1-3_{or cancer}4,5_{. T cells are vital}

ĨŽƌƚŚĞŚŽŵĞŽƐƚĂƐŝƐŽĨƚŚĞŝŵŵƵŶĞƐǇƐƚĞŵ͕ĂŶĚƚŚĞƌĞĨŽƌĞĂƌĞĂƚĂƌŐĞƚĨŽƌƚƌĞĂƟŶŐƐƵĐŚ diseases6-8_{. In this thesis, we have focused on the treatment of diseases in which T cells}

ĂƌĞƚŽŽĂĐƟǀĞ;ĂƚŚĞƌŽƐĐůĞƌŽƐŝƐͿŽƌŶŽƚƐƵĸĐŝĞŶƚůǇĂĐƟǀĂƚĞĚ;ĐĂŶĐĞƌͿĂŶĚƉƌŽƉŽƐĞŶĞǁ treatment strategies using liposomes, which is introduced in ĐŚĂƉƚĞƌϭ.

>ŝƉŽƐŽŵĞƐ ĂƌĞ ǀĞƌƐĂƟůĞ ǀĞƐŝĐůĞͲůŝŬĞ ƐƚƌƵĐƚƵƌĞƐ͕ ƚŚĂƚ ĐĂŶ ďĞ ĞŶŐŝŶĞĞƌĞĚ ŝŶƚŽ various physical forms. In ĐŚĂƉƚĞƌϮǁĞƌĞǀŝĞǁĞĚŚŽǁƉĂƌƟĐůĞƐŝǌĞ͕ƐŚĂƉĞ͕ĂŶĚƌŝŐŝĚŝƚǇŽĨ

ƉĂƌƟĐƵůĂƚĞǀĂĐĐŝŶĞƐĂīĞĐƚďŝŽĚŝƐƚƌŝďƵƟŽŶ͕ĐĞůůƵůĂƌƵƉƚĂŬĞ͕ĂŶƟŐĞŶƉƌĞƐĞŶƚĂƟŽŶĂŶĚƚŚĞ ƌĞƐƵůƟŶŐŝŵŵƵŶĞƌĞƐƉŽŶƐĞ͘tŚŝůĞƚŚĞƌĞĂƌĞƚƌĞŶĚƐƚŚĂƚĐĂŶďĞŽďƐĞƌǀĞĚďĞƚǁĞĞŶƚŚĞ ƉŚǇƐŝĐŽĐŚĞŵŝĐĂůƉĂƌĂŵĞƚĞƌƐŽĨƐƵĐŚǀĂĐĐŝŶĞƐĂŶĚƚŚĞƌĞƐƵůƟŶŐŝŵŵƵŶĞƌĞƐƉŽŶƐĞƐ͕ŝƚŝƐ ŽŌĞŶǀĞƌǇĚŝĸĐƵůƚƚŽĂůƚĞƌũƵƐƚŽŶĞƉĂƌĂŵĞƚĞƌǁŝƚŚŽƵƚĂīĞĐƟŶŐŽƚŚĞƌƐ͘,ŽǁĞǀĞƌ͕ŝƚŝƐ ĐůĞĂƌƚŚĂƚĂƌĂƟŽŶĂůĚĞƐŝŐŶĂƉƉƌŽĂĐŚŝƐŶĞĐĞƐƐĂƌǇƚŽŽƉƟŵŝǌĞĂǀĂĐĐŝŶĞĨŽƌĂƐƉĞĐŝĮĐƵƐĞ͖ ƚŚĞƉŚǇƐŝĐŽĐŚĞŵŝĐĂůƉĂƌĂŵĞƚĞƌƐĨŽƌŽƉƟŵĂůĂŶƟŐĞŶͲƉƌĞƐĞŶƟŶŐĐĞůů;WͿƵƉƚĂŬĞŵĂǇ ŶŽƚďĞŝĚĞĂůĨŽƌĞůŝĐŝƟŶŐƚŚĞĚĞƐŝƌĞĚŝŵŵƵŶĞƌĞƐƉŽŶƐĞ͘/ŶůĂƚĞƌĐŚĂƉƚĞƌƐ͕ƚŚŝƐŝƐĂůǁĂǇƐ considered and studied in detail when designing the liposomes.

In ĐŚĂƉƚĞƌϯǁĞĂŝŵĞĚƚŽƵŶĚĞƌƐƚĂŶĚƚŚĞĞīĞĐƚŽĨůŝƉŽƐŽŵĂůƌŝŐŝĚŝƚǇ͕ŽŶĞŽĨƚŚĞŵŽƐƚ ŽǀĞƌͲůŽŽŬĞĚƉĂƌĂŵĞƚĞƌƐĨŽƌŶĂŶŽƉĂƌƟĐůĞƐ͕ŽŶĂŶƟŐĞŶͲƐƉĞĐŝĮĐdĐĞůůƌĞƐƉŽŶƐĞƐ͘KŶĞŽĨ ƚŚĞƌĞĂƐŽŶƐƚŚĂƚƌŝŐŝĚŝƚǇŚĂƐŶŽƚďĞĞŶƐƚƵĚŝĞĚĂƐĞǆƚĞŶƐŝǀĞůǇĂƐŽƚŚĞƌƉŚǇƐŝĐŽĐŚĞŵŝĐĂů ƉĂƌĂŵĞƚĞƌƐŝƐƚŚĞĚŝĸĐƵůƚǇŝŶĂĐĐƵƌĂƚĞůǇŵĞĂƐƵƌŝŶŐŝƚ9-14_{͕ĂŶĚĂůĂĐŬŽĨƐƚĂŶĚĂƌĚŝǌĂƟŽŶ} ŝŶƚŚĞůŝƚĞƌĂƚƵƌĞ͘tĞƵƐĞĚĂƚŽŵŝĐĨŽƌĐĞŵŝĐƌŽƐĐŽƉǇ;&DͿƚŽĂĐĐƵƌĂƚĞůǇŵĞĂƐƵƌĞƚŚĞ ƌŝŐŝĚŝƚǇ ŽĨ ŝŶĚŝǀŝĚƵĂů ĂŶŝŽŶŝĐ ůŝƉŽƐŽŵĞƐ ĐŽŶƚĂŝŶŝŶŐ ĂŶ ŽǀĂůďƵŵŝŶͲĚĞƌŝǀĞĚ ϰ+_{T cell} ĞƉŝƚŽƉĞ͘ dŚĞ ƐƵƌĨĂĐĞ ĐŚĂƌŐĞ͕ ƉŚŽƐƉŚŽůŝƉŝĚ ŚĞĂĚ ŐƌŽƵƉ ĐŽŵƉŽƐŝƟŽŶ͕ ĂŶƟŐĞŶ ĐŽŶƚĞŶƚ ĂŶĚ ƐŝǌĞ ŽĨ ƚŚĞ ůŝƉŽƐŽŵĞƐ ǁĞƌĞ ĐŽŶƚƌŽůůĞĚ ŝŶ ŽƌĚĞƌ ƚŽ ŵŝŶŝŵŝǌĞ ĂůƚĞƌĂƟŽŶƐ ŝŶ ŽƚŚĞƌ ƉŚǇƐŝĐŽĐŚĞŵŝĐĂůƉĂƌĂŵĞƚĞƌƐ͘tĞĨŽƵŶĚƚŚĂƚƚŚĞŝŶĐŽƌƉŽƌĂƟŽŶŽĨĐŚŽůĞƐƚĞƌŽůŝŶƚŚĞůŝƉŝĚ ďŝůĂǇĞƌĚĞĐƌĞĂƐĞƐƚŚĞƌŝŐŝĚŝƚǇŽĨŐĞůͲƐƚĂƚĞůŝƉŽƐŽŵĞƐĂŶĚŝŶĐƌĞĂƐĞƐƚŚĂƚŽĨŇƵŝĚͲƐƚĂƚĞŽŶĞƐ͘ &ƵƌƚŚĞƌŵŽƌĞ͕ ƚŚĞ ƚƌĂŶƐŝƟŽŶ ƚĞŵƉĞƌĂƚƵƌĞ ŽĨ ƚŚĞ ƉŚŽƐƉŚŽůŝƉŝĚƐ ŝŶŇƵĞŶĐĞĚ ƚŚĞ ŽǀĞƌĂůů ůŝƉŽƐŽŵĞ ƌŝŐŝĚŝƚǇ͘ /ŶƚĞƌĞƐƟŶŐůǇ͕ ĂůŵŽƐƚ Ăůů ĨŽƌŵƵůĂƟŽŶƐ ƐŚŽǁĞĚ Ă ƉŽƐŝƟǀĞ ĐŽƌƌĞůĂƟŽŶ ďĞƚǁĞĞŶůŝƉŽƐŽŵĂůƌŝŐŝĚŝƚǇĂŶĚWĂƐƐŽĐŝĂƟŽŶ͘,ŽǁĞǀĞƌ͕ĚŝŽůĞŽǇůƉŚŽƐƉŚĂƟĚǇůĐŚŽůŝŶĞ ;KWͿ͗ĚŝŽůĞŽǇůƉŚŽƐƉŚĂƟĚǇůŐůǇĐĞƌŽů;KW'ͿůŝƉŽƐŽŵĞƐƐŚŽǁĞĚƚŚĞŚŝŐŚĞƐƚĂƐƐŽĐŝĂƟŽŶ ƚŽ ĚĞŶĚƌŝƟĐ ĐĞůůƐ ;ƐͿ ŽĨ Ăůů ƚĞƐƚĞĚ ĨŽƌŵƵůĂƟŽŶƐ ĚĞƐƉŝƚĞ ŚĂǀŝŶŐ ƚŚĞ ůŽǁĞƐƚ ƌŝŐŝĚŝƚǇ͕ ŝŶĚŝĐĂƟŶŐ ƚŚĂƚ ůŝƉŽƐŽŵĂů ƌŝŐŝĚŝƚǇ ĂůŽŶĞ ĚŽĞƐ ŶŽƚ ĐŽŶƚƌŽů W ƵƉƚĂŬĞ͘ tĞ ĚŝĚ ŽďƐĞƌǀĞ ĂƐŝŐŶŝĮĐĂŶƚĐŽƌƌĞůĂƟŽŶďĞƚǁĞĞŶƚŚĞƌŝŐŝĚŝƚǇŽĨƚŚĞůŝƉŽƐŽŵĞƐĂŶĚƚŚĞƌĞŐƵůĂƚŽƌǇdĐĞůů ;dƌĞŐͿƌĞƐƉŽŶƐĞƐƚŚĞǇĞůŝĐŝƚĞĚin vitro and in vivo͘KƵƌĮŶĚŝŶŐƐŵĂǇĐŽŶƚƌŝďƵƚĞƚŽĂďĞƩĞƌ ƵŶĚĞƌƐƚĂŶĚŝŶŐ ŽĨ ƚŚĞ ĨĂĐƚŽƌƐ ĚƌŝǀŝŶŐ dƌĞŐ ƌĞƐƉŽŶƐĞƐ͕ ĂŶĚ ƐƵƉƉŽƌƚ Ă ƌĂƟŽŶĂů ĚĞƐŝŐŶ ŽĨ ůŝƉŽƐŽŵĂů ĂƐ ǁĞůů ĂƐ ŽƚŚĞƌ ŶĂŶŽƉĂƌƟĐƵůĂƚĞ ǀĂĐĐŝŶĞ ĨŽƌŵƵůĂƟŽŶƐ ĂŝŵŝŶŐ ƚŽ ĞŶŚĂŶĐĞ ĂŶƟŐĞŶͲƐƉĞĐŝĮĐdƌĞŐƌĞƐƉŽŶƐĞƐĨŽƌƚŚĞƚƌĞĂƚŵĞŶƚŽĨĂƵƚŽŝŵŵƵŶĞĚŝƐĞĂƐĞƐ͘

ƵŝůĚŝŶŐƵƉŽŶƚŚĞŝŶĨŽƌŵĂƟŽŶƉƌĞƐĞŶƚĞĚŝŶĐŚĂƉƚĞƌƐϮand ϯ, ĐŚĂƉƚĞƌƐϰ and ϱ focus on using liposomes to treat atherosclerosis. Atherosclerosis is the predominant ƵŶĚĞƌůǇŝŶŐƉĂƚŚŽůŽŐǇŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ͕ǁŚŝĐŚĂīĞĐƚƐŵŝůůŝŽŶƐŽĨƉĞŽƉůĞǁŽƌůĚͲ wide15_{͘>ŝƉŝĚƐŝŶƚŚĞĨŽƌŵŽĨůŽǁͲĚĞŶƐŝƚǇůŝƉŽƉƌŽƚĞŝŶ;>>ͿĂĐĐƵŵƵůĂƚĞŝŶƚŚĞƐƵďĞŶĚŽƚŚĞůŝĂů} ƐƉĂĐĞŝŶŵĞĚŝƵŵͲĂŶĚůĂƌŐĞͲƐŝǌĞĚĂƌƚĞƌŝĞƐ͕ǁŚŝĐŚůĞĂĚƐƚŽĐŚƌŽŶŝĐŝŶŇĂŵŵĂƟŽŶ16_{. LDL} ĐĂŶŵŽĚŝĨǇƚŽĨŽƌŵŽǆŝĚŝǌĞĚ>>;Žǆ>>Ϳ͕ǁŚŝĐŚĂƩƌĂĐƚƐŝŵŵƵŶĞĐĞůůƐ͕ĐŽŶƟŶƵŝŶŐƚŚĞ ŝŶŇĂŵŵĂƟŽŶ16_{͘^ŽŵĞŽĨƚŚĞƐĞŝŵŵƵŶĞĐĞůůƐ͕ƐƵĐŚĂƐŵŽŶŽĐǇƚĞƐ͕ĐĂŶĚŝīĞƌĞŶƟĂƚĞŝŶƚŽ} ŵĂĐƌŽƉŚĂŐĞƐǁŚŝĐŚĐĂŶƉŚĂŐŽĐǇƚŽƐĞŽǆ>>͕ůĞĂĚŝŶŐƚŽĨŽĂŵĐĞůůĨŽƌŵĂƟŽŶ17_{͘DĂŶŝƉƵůĂƟŽŶ}

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atherosclerosis. In ĐŚĂƉƚĞƌϰ we designed liposomes that can induce Tregs. Liposomes

ǁĞƌĞĐŽŵƉŽƐĞĚŽĨĚŝƐƚĞĂƌŽǇůƉŚŽƐƉŚĂƟĚǇůĐŚŽůŝŶĞ;^WͿ͗ĚŝƐƚĞĂƌŽǇůƉŚŽƐƉŚĂƟĚǇůŐůǇĐĞƌŽů ;^W'Ϳ͗ĐŚŽůĞƐƚĞƌŽů;,K>Ϳ;ĂůƐŽŽŶĞŽĨƚŚĞŵŽƐƚƌŝŐŝĚĂŶĚƉŽƚĞŶƚĨŽƌŵƵůĂƟŽŶƐŝŶĐŚĂƉƚĞƌ

ϯͿ ĂŶĚ ǁĞƌĞ ůŽĂĚĞĚ ǁŝƚŚ ĂŶ ŽǀĂůďƵŵŝŶͲĚĞƌŝǀĞĚ ϰ+_{T cell epitope. These liposomes}

ǁĞƌĞ ƐŚŽǁŶ ƚŽ ĞůŝĐŝƚ ŚŝŐŚ ƉƌŽĚƵĐƟŽŶ ŽĨ ĂŶƟŐĞŶͲƐƉĞĐŝĮĐ dƌĞŐƐ in vitro and in vivo in ŵŝĐĞ ĂƐ ĐŽŵƉĂƌĞĚ ƚŽ ĨƌĞĞ ĂŶƟŐĞŶ͕ ^W͗ĚŝƉĂůŵŝƚŽǇůƉŚŽƐƉŚĂƟĚǇůƐĞƌŝŶĞ ;WW^Ϳ͗,K>͕ ĂŶĚ ^W͗ĚŝƉĂůŵŝƚŽǇůƚƌŝŵĞƚŚǇůĂŵŵŽŶŝƵŵƉƌŽƉĂŶĞ ;WdWͿ͗,K> ůŝƉŽƐŽŵĞƐ͘ Ɛ ĂŶ ĂƚŚĞƌŽƐĐůĞƌŽƐŝƐͲƐƉĞĐŝĮĐ ĂŶƟŐĞŶ͕ ǁĞ ƚƵƌŶĞĚ ƚŽ ƉŽϭϬϬ͕ ƚŚĞ ƉƌŽƚĞŝŶ ĐŽŵƉŽŶĞŶƚ ŽĨ Žǆ>>͕ ǁŚŝĐŚ ǁĂƐ ĂůƌĞĂĚǇ ƐŚŽǁŶ ƚŽ ďĞ Ă ƌĞůĞǀĂŶƚ ĂŶƟŐĞŶ20-31_{͘ tĞ ŝĚĞŶƟĮĞĚ Ă ŵĂũŽƌͲ} ŚŝƐƚŽĐŽŵƉĂƟďŝůŝƚǇĐŽŵƉůĞǆ;D,ͿͲ//ͲƌĞƐƚƌŝĐƚĞĚƉŽϭϬϬͲĚĞƌŝǀĞĚƉĞƉƟĚĞ͕ƌĞĨĞƌƌĞĚƚŽĂƐ ƉϯϱϬϬ͕ƵƐŝŶŐĂƉĞƉƟĚŽŵŝĐƐƐƚƌĂƚĞŐǇ͘tŚĞŶĞŶĐĂƉƐƵůĂƟŶŐƉϯϱϬϬŝŶ^W'ͲůŝƉŽƐŽŵĞƐŝƚ ƐƵĐĐĞƐƐĨƵůůǇƌĞĚƵĐĞĚĂƚŚĞƌŽƐĐůĞƌŽƟĐƉůĂƋƵĞĨŽƌŵĂƟŽŶ͕ĂƐŵĞĂƐƵƌĞĚďǇĂƌĞĚƵĐƟŽŶŝŶ ƚŽƚĂůƉůĂƋƵĞƐŝǌĞ͕ĂŶĚĂŶŝŶĐƌĞĂƐĞŝŶƉůĂƋƵĞƐƚĂďŝůŝƚǇ͘ tĞĂůƐŽĚĞƐĐƌŝďĞĚƚŚĞŵĞĐŚĂŶŝƐŵďĞŚŝŶĚƚŚĞƉŽƚĞŶĐǇŽĨƚŚĞ^W'ͲůŝƉŽƐŽŵĞƐ͘ /ŶƚĞƌĞƐƟŶŐůǇ͕ ŝƚ ŚĂƐ ďĞĞŶ ƐŚŽǁŶ ƚŚĂƚ ĂŶŝŽŶŝĐ ůŝƉŽƐŽŵĞƐ ĐŽŵƉŽƐĞĚ ŽĨ W^ ƌĞƐĞŵďůĞ ĂƉŽƉƚŽƟĐĐĞůůƐ͕ƐŝŶĐĞW^ďĞĐŽŵĞƐĞǆƉŽƐĞĚŽŶƚŚĞƐƵƌĨĂĐĞŽĨĂƉŽƉƚŽƟĐĐĞůůƐ32_{. Through} ƐĐĂǀĞŶŐĞƌƌĞĐĞƉƚŽƌ;^ZͿͲŵĞĚŝĂƚĞĚƵƉƚĂŬĞďǇWƐ͕W^ͲĐŽŶƚĂŝŶŝŶŐůŝƉŽƐŽŵĞƐĐĂŶŵĞĚŝĂƚĞ ĂŶ ĂŶƟͲŝŶŇĂŵŵĂƚŽƌǇ ĞīĞĐƚ33,34_{͘ tĞ ƐŚŽǁ ƚŚĂƚ ^W'ͲůŝƉŽƐŽŵĞƐ ĂƌĞ ŵŽƌĞ ĞīĞĐƟǀĞůǇ} ƚĂŬĞŶ ƵƉ ďǇ Ɛ in vitro ƚŚĂŶ WW^ͲůŝƉŽƐŽŵĞƐ͘ tĞ ĂůƐŽ ĚĞŵŽŶƐƚƌĂƚĞ Ă ƌŽůĞ ĨŽƌ ƚŚĞ ƉƌŽƚĞŝŶ ĐŽƌŽŶĂ ŝŶ dƌĞŐ ŝŶĚƵĐƟŽŶ ǀŝĂ ^ZƐ͘ In vitro and in vivo, liposomes interact with ƉƌŽƚĞŝŶƐ ŝŶ ƚŚĞ ƉŚǇƐŝŽůŽŐŝĐĂů ŵĞĚŝƵŵ͕ ƌĞƐƵůƟŶŐ ŝŶ ƚŚĞ ĨŽƌŵĂƟŽŶ ŽĨ Ă ƉƌŽƚĞŝŶ ĐŽƌŽŶĂ around the liposomes35_{͘tĞĨŽƵŶĚĂƐŝŐŶŝĮĐĂŶƚƌĞĚƵĐƟŽŶŽĨƵƉƚĂŬĞĨŽƌďŽƚŚW'ͲĂŶĚ}

W^ͲůŝƉŽƐŽŵĞƐŝŶƚŚĞƉƌĞƐĞŶĐĞŽĨƐĞƌƵŵǁŚĞŶ^ZͲŵĞĚŝĂƚĞĚƵƉƚĂŬĞďǇƐǁĂƐďůŽĐŬĞĚ͕ ǁŚŝĐŚǁĂƐŶŽƚŽďƐĞƌǀĞĚŝŶƐĞƌƵŵͲĨƌĞĞĐŽŶĚŝƟŽŶƐ͕ƐƵŐŐĞƐƟŶŐƚŚĂƚĨŽƌŵĂƟŽŶŽĨĂƉƌŽƚĞŝŶ ĐŽƌŽŶĂŝƐƌĞƋƵŝƌĞĚĨŽƌůŝƉŽƐŽŵĞͲ^ZŝŶƚĞƌĂĐƟŽŶƐ͘tĞĐŽŶĐĞŶƚƌĂƚĞĚŽŶƚŚĞƐĞƌƵŵƉƌŽƚĞŝŶ ĐŽŵƉůĞŵĞŶƚĐŽŵƉŽŶĞŶƚϭY;ϭƋͿ͕ƐŝŶĐĞŝƚǁĂƐƐŚŽǁŶƚŽďŝŶĚƚŽW^ŽŶĂƉŽƉƚŽƟĐĐĞůůƐ and lead to clearance via SRs36-39_{͘/ŶƚĞƌĞƐƟŶŐůǇ͕ϭƋŝƐĂůƐŽŝŶǀŽůǀĞĚŝŶƚŚĞƉĂƚŚŽůŽŐǇŽĨ}

atherosclerosis40_{͘ tĞ ƐŚŽǁĞĚ ƚŚĂƚ ϭƋ ŝƐ ƉƌĞƐĞŶƚ ŝŶ ƚŚĞ ƉƌŽƚĞŝŶ ĐŽƌŽŶĂ ĂŶĚ ďŝŶĚƐ ƚŽ} ĂŶŝŽŶŝĐ ůŝƉŽƐŽŵĞƐ͘ dŚĞ ĂĚĚŝƟŽŶ ŽĨ ϭƋ ŝŶ ƐĞƌƵŵͲĨƌĞĞ ĐŽŶĚŝƟŽŶƐ ĐŽŵƉůĞƚĞůǇ ƌĞƐƚŽƌĞĚ ƚŚĞ ƵƉƚĂŬĞ ŽĨ ďŽƚŚ W'Ͳ ĂŶĚ W^ͲůŝƉŽƐŽŵĞƐ͕ ǁŚŝůĞ ƐƉĞĐŝĮĐ ĚĞƉůĞƟŽŶ ŽĨ ϭƋ ŝŶ ƐĞƌƵŵ ƐŝŐŶŝĮĐĂŶƚůǇƌĞĚƵĐĞĚƵƉƚĂŬĞŽĨW'ͲůŝƉŽƐŽŵĞƐ͘tĞĨƵƌƚŚĞƌŽďƐĞƌǀĞĚƚŚĂƚƚŚĞĂĚĚŝƟŽŶŽĨ ϭƋŝŶĐƌĞĂƐĞƐdƌĞŐƌĞƐƉŽŶƐĞƐĐŽŵƉĂƌĞĚƚŽƐĞƌƵŵͲĨƌĞĞĐŽŶĚŝƟŽŶƐ͕ďƵƚŶŽƚƐŝŐŶŝĮĐĂŶƚůǇ͘ dŚŝƐƐƵŐŐĞƐƚƐƚŚĂƚϭƋŝƐƉĂƌƟĂůůǇƌĞƐƉŽŶƐŝďůĞĨŽƌƚŚĞdƌĞŐŝŶĚƵĐƟŽŶŽĨďŽƚŚ^W'ͲĂŶĚ WW^ͲůŝƉŽƐŽŵĞƐ͕ ďƵƚ ƚŚĞ ƉƌŽƚĞŝŶ ĐŽƌŽŶĂ ůŝŬĞůǇ ĐŽŶƚĂŝŶƐ ŵŽƌĞ ĐŽŵƉŽŶĞŶƚƐ ƚŚĂƚ ŚĞůƉ ƚŽŝŶĚƵĐĞdƌĞŐƐ͘&ƵƌƚŚĞƌŵŽƌĞ͕ŝƚǁŽƵůĚďĞǀĞƌǇŝŶƚĞƌĞƐƟŶŐƚŽƐƚƵĚǇǁŚĞƚŚĞƌƚŚĞƌĞŝƐĂ ƌĞůĂƟŽŶƐŚŝƉďĞƚǁĞĞŶůŝƉŽƐŽŵĂůƌŝŐŝĚŝƚǇĂŶĚƚŚĞƉƌŽƚĞŝŶĐŽƌŽŶĂ͕ǁŚŝĐŚŝƐƐŽŵĞƚŚŝŶŐǁĞ have not studied.

ϭƋĚŽĞƐŶŽƚŽŶůǇŝŶƚĞƌĂĐƚǁŝƚŚ^ZƐ͕ďƵƚĂůƐŽďŝŶĚƐƚŽŽƚŚĞƌƉƌŽƚĞŝŶƐ͕ƐƵĐŚĂƐƚŚĞ ϭƋͲďŝŶĚŝŶŐƉƌŽƚĞŝŶ͕ĂůƐŽŬŶŽǁŶĂƐƉϯϮ͘dŚŝƐƌĞĐĞƉƚŽƌŝƐĂďĞƌƌĂŶƚůǇĞǆƉƌĞƐƐĞĚŝŶƉůĂƋƵĞͲ resident macrophages41_{͘ƐŵĞŶƟŽŶĞĚĂďŽǀĞ͕ŵĂĐƌŽƉŚĂŐĞƐƉůĂǇĂŶŝŵƉŽƌƚĂŶƚƌŽůĞŝŶ}

the pathogenesis of atherosclerosis, since they can phagocytose lipids and become large lipid-rich foam cells42_{. These foam cells are unable to migrate out of the vessel wall, leading}

ƚŽĂďƵŝůĚͲƵƉĂƚƚŚĞƐŝƚĞŽĨƚŚĞŝŶŇĂŵŵĂƟŽŶĂŶĚĨŽƌŵĂƟŽŶŽĨĂƉůĂƋƵĞ43_{. Therefore, a}

ƐƵŝƚĂďůĞƚƌĞĂƚŵĞŶƚƐƚƌĂƚĞŐǇǁŽƵůĚďĞƚŽƉƌĞǀĞŶƚĂŶĚͬŽƌƌĞǀĞƌƐĞƚŚĞĨŽƌŵĂƟŽŶŽĨĨŽĂŵ cells19_{, which was our goal in}_{ĐŚĂƉƚĞƌϱ. Macrophages are able to reverse cholesterol}

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7

'ϭ44_{͘dŚĞĞǆƉƌĞƐƐŝŽŶŽĨďŽƚŚŽĨƚŚĞƐĞƚƌĂŶƐƉŽƌƚĞƌƐŝƐĐŽŶƚƌŽůůĞĚďǇƚŚĞůŝǀĞƌyƌĞĐĞƉƚŽƌ}

;>yZͿ͘ĐůĂƐƐŽĨƐŵĂůůŵŽůĞĐƵůĞƐ͕ĐĂůůĞĚ>yZĂŐŽŶŝƐƚƐ;e.g.͕'tϯϵϲϱͿ͕ĐĂŶĂĐƟǀĂƚĞƚŚŝƐ ƌĞĐĞƉƚŽƌ ƚŽ ŝŶĚƵĐĞ ƌĞǀĞƌƐĞ ĐŚŽůĞƐƚĞƌŽů ƚƌĂŶƐƉŽƌƚ ŝŶ ĨŽĂŵ ĐĞůůƐ͕ ĂůůŽǁŝŶŐ ĨŽƌ ŵŝŐƌĂƟŽŶ ŽĨ ƚŚĞƐĞ ĐĞůůƐ ĨƌŽŵ ƚŚĞ ƉůĂƋƵĞ45_{. Unfortunately, when administered systemically at}

ƚŚĞƌĂƉĞƵƟĐĚŽƐĞƐ͕>yZĂŐŽŶŝƐƚƐŚĂǀĞĞīĞĐƚƐŝŶŽƚŚĞƌŽƌŐĂŶƐ͕ƐƵĐŚĂƐƚŚĞůŝǀĞƌ͕ůĞĂĚŝŶŐ to high triglyceride levels in the plasma or liver46-48_{͘ŶĐĂƉƐƵůĂƟŽŶŽĨƚŚĞ>yZĂŐŽŶŝƐƚŝŶĂ}

drug delivery vehicle such as liposomes can overcome this problem49_{͘dŚĞĐǇĐůŝĐƉĞƉƟĚĞ}

>ǇƉͲϭ;'E<ZdZ'ͿďŝŶĚƐƚŽƉϯϮĂŶĚĐĂŶƚŚĞƌĞĨŽƌĞďĞƵƐĞĚƚŽƚĂƌŐĞƚŵĂĐƌŽƉŚĂŐĞƐŝŶ ĂƚŚĞƌŽƐĐůĞƌŽƟĐůĞƐŝŽŶƐ50,51_{͘&ŽƌƚŚŝƐƉƵƌƉŽƐĞ͕ǁĞĚĞƐŝŐŶĞĚĂƉĂƌƟĐƵůĂƚĞĨŽƌŵƵůĂƟŽŶƚŚĂƚ} ĐŽŵďŝŶĞƐƚŚĞƚĂƌŐĞƟŶŐƉƌŽƉĞƌƟĞƐŽĨƚŚĞĐǇĐůŝĐƉĞƉƟĚĞ>ǇƉͲϭǁŝƚŚƚŚĞƚŚĞƌĂƉĞƵƟĐĞīĞĐƚ ŽĨĂŶ>yZĂŐŽŶŝƐƚ;'tϯϵϲϱͿĂŶĚƉƌŽŵŽƚĞƐƌĞǀĞƌƐĞĐŚŽůĞƐƚĞƌŽůƚƌĂŶƐƉŽƌƚŝŶĨŽĂŵĐĞůůƐƚŽ ƐƚĂďŝůŝǌĞĂƚŚĞƌŽƐĐůĞƌŽƟĐƉůĂƋƵĞƐ͘tĞƵƐĞĚƚŚĞŬŶŽǁůĞĚŐĞŐĂŝŶĞĚĨƌŽŵĐŚĂƉƚĞƌϮ, ĐŚĂƉƚĞƌ ϯandĐŚĂƉƚĞƌϰƚŽĨŽƌŵƵůĂƚĞůŝƉŽƐŽŵĞƐǁŝƚŚůŽŶŐĐŝƌĐƵůĂƟŽŶƟŵĞ͕ŵŝŶŝŵĂůWƵƉƚĂŬĞ͕ ĂŶĚŵŝŶŝŵĂůŝŵŵƵŶĞĞīĞĐƚƐ͘tĞƚŚĞŶĨƵŶĐƟŽŶĂůŝǌĞĚƚŚĞůŝƉŽƐŽŵĞƐǁŝƚŚ>ǇƉͲϭ͕ĂŶĚƚŚŝƐ ůĞĚƚŽŐƌĞĂƚůǇĞŶŚĂŶĐĞĚĂƐƐŽĐŝĂƟŽŶƚŽĨŽĂŵĐĞůůƐin vitro͕ǁŚŝůĞŚĂǀŝŶŐůŝŵŝƚĞĚĂĸŶŝƚǇĨŽƌ macrophages. In vivoǁĞƐĂǁƌĞƚĞŶƟŽŶŽĨůŝƉŽƐŽŵĞƐŝŶĂƚŚĞƌŽƐĐůĞƌŽƟĐƉůĂƋƵĞƐ͕ĂŶĚǁĞ ĐŽŶĮƌŵĞĚƚŚĂƚƚŚĞƉůĂƋƵĞͲƌĞƐŝĚĞŶƚĨŽĂŵĐĞůůƐŚĂĚƚĂŬĞŶƵƉƚŚĞƚĂƌŐĞƚĞĚůŝƉŽƐŽŵĞƐ͘tĞ ƐŚŽǁĞĚƚŚĂƚƵƐŝŶŐĂůŽǁĚŽƐĞŽĨ'tϯϵϲϱĞŶĐĂƉƐƵůĂƚĞĚŝŶ>ǇƉͲϭůŝƉŽƐŽŵĞƐĐĂŶƌĞĚƵĐĞ ƉůĂƋƵĞŵĂĐƌŽƉŚĂŐĞĐŽŶƚĞŶƚĂŶĚŝŶĐƌĞĂƐĞƉůĂƋƵĞƐƚĂďŝůŝƚǇǁŚŝůĞĂǀŽŝĚŝŶŐĂŶŝŶĐƌĞĂƐĞŝŶ ůŝƉŝĚƐŝŶƚŚĞƐĞƌƵŵĂŶĚůŝǀĞƌ͘dŚĞƐĞĮŶĚŝŶŐƐĚĞŵŽŶƐƚƌĂƚĞƚŚĂƚŝƚŝƐƉŽƐƐŝďůĞƚŽŝŶĐƌĞĂƐĞ ƚŚĞ ƚŚĞƌĂƉĞƵƟĐ ǁŝŶĚŽǁ ŽĨ >yZ ĂŐŽŶŝƐƚƐ͕ ĂŶĚ ŵĂǇ ĐŽŶƚƌŝďƵƚĞ ƚŽ ƚŚĞ ĚĞƐŝŐŶ ŽĨ ŽƚŚĞƌ ĂƚŚĞƌŽƐĐůĞƌŽƐŝƐƚŚĞƌĂƉŝĞƐ͘/ŶƉĂƌƟĐƵůĂƌ͕>ǇƉͲϭͲĨƵŶĐƟŽŶĂůŝǌĞĚůŝƉŽƐŽŵĞƐĐŽƵůĚďĞƵƐĞĚĂƐ ĂƉůĂƞŽƌŵƚŽĚĞůŝǀĞƌŽƚŚĞƌĐŽŵƉŽƵŶĚƐ͕ƐƵĐŚĂƐĂŶƟͲŝŶŇĂŵŵĂƚŽƌǇĚƌƵŐƐ͕ƚŽĨŽĂŵĐĞůůƐ͘ dŚĞĮŶĂůƌĞƐĞĂƌĐŚĐŚĂƉƚĞƌŽĨƚŚŝƐƚŚĞƐŝƐ;ĐŚĂƉƚĞƌϲͿĨŽĐƵƐĞƐŽŶƵƐŝŶŐůŝƉŽƐŽŵĞƐ to treat cancer, which is another major health concern52_{͘ĂŶĐĞƌĞŶĐŽŵƉĂƐƐĞƐĂŐƌŽƵƉ}

ŽĨĚŝƐĞĂƐĞƐŝŶǀŽůǀŝŶŐĂďŶŽƌŵĂůƐƵƐƚĂŝŶĞĚĐĞůůƉƌŽůŝĨĞƌĂƟŽŶ͕ƌĞƉůŝĐĂƟŽŶ͕ĂŶĚƐƵƌǀŝǀĂů53_{. T} ĐĞůůƐĂƌĞĂůƐŽŝŶǀŽůǀĞĚŝŶĐĂŶĐĞƌ͕ƐŝŶĐĞƚŚĞǇĐĂŶƌĞĐŽŐŶŝǌĞƚƵŵŽƌͲĂƐƐŽĐŝĂƚĞĚĂŶƟŐĞŶƐ4,5_, ŚŽǁĞǀĞƌ ŝŶ ĐŽŶƚƌĂƐƚ ƚŽ ĂƚŚĞƌŽƐĐůĞƌŽƐŝƐ͕ d ĐĞůů ƌĞƐƉŽŶƐĞƐ ŝŶ ĐĂŶĐĞƌ ĂƌĞ ŶŽƚ ĞīĞĐƟǀĞ ĂŶĚ ƐƵīĞƌ ĨƌŽŵ ĞǆŚĂƵƐƟŽŶ54_{. As we have shown in}_{ĐŚĂƉƚĞƌ ϰ͕ ^W͗WdW͗,K>} ůŝƉŽƐŽŵĞƐ ĂƌĞ ƉŽƚĞŶƚ Ăƚ ŝŶĚƵĐŝŶŐ ĂŶƟŐĞŶͲƐƉĞĐŝĮĐ ƉƌŽͲŝŶŇĂŵŵĂƚŽƌǇ d ĐĞůůƐ ĂŶĚ ŵĂǇ ƉƌŽǀŝĚĞƚŚĞƚǇƉĞŽĨŝŵŵƵŶĞƌĞƐƉŽŶƐĞƌĞƋƵŝƌĞĚƚŽŬŝůůĂƚƵŵŽƌ͘/ŶĐŚĂƉƚĞƌϲ we aimed ƚŽ ƌĞƉƵƌƉŽƐĞ ^W͗WdW͗,K> ůŝƉŽƐŽŵĞƐ ǁŝƚŚ ƚƵŵŽƌ ŶĞŽĞƉŝƚŽƉĞƐ ĂƐ Ă ƚŚĞƌĂƉĞƵƟĐ ĐĂŶĐĞƌǀĂĐĐŝŶĞ͘EĞŽĞƉŝƚŽƉĞƐĂƌĞǀĞƌǇŝŶƚĞƌĞƐƟŶŐĨŽƌƚƌĞĂƚŵĞŶƚ͖ƚŚĞǇƌĞƐƵůƚĨƌŽŵŶŽŶͲ ƐǇŶŽŶǇŵŽƵƐƐŽŵĂƟĐŵƵƚĂƟŽŶƐƚŚĂƚĞŶĐŽĚĞŶĞǁĂŵŝŶŽĂĐŝĚƌĞƐŝĚƵĞƐ͕ůĞĂĚŝŶŐƚŽŶŽǀĞů ƉĞƉƟĚĞƐ ƚŚĂƚ ĐĂŶ ďĞ ƉƌĞƐĞŶƚĞĚ ŽŶ ƚŚĞ ĐĞůů ƐƵƌĨĂĐĞ ŽĨ ƚƵŵŽƌ ĐĞůůƐ55_{. The Hannover} DĞĚŝĐĂů ^ĐŚŽŽů ƉƌĞǀŝŽƵƐůǇ ƐŚŽǁĞĚ ƚŚĂƚ ŝŶĚƵĐŝŶŐ ƐƚƌŽŶŐ ƉƌŽͲŝŶŇĂŵŵĂƚŽƌǇ d ĐĞůů responses against Adpgk_mut ;Ă ŶĞŽĞƉŝƚŽƉĞͿ ĐŽƵůĚ ĞůŝŵŝŶĂƚĞ ĞƐƚĂďůŝƐŚĞĚ ĐĂŶĐĞƌƐ56_{. This}

ǁĂƐĂĐŚŝĞǀĞĚďǇŝƐŽůĂƟŶŐƐĨƌŽŵŵŝĐĞ͕ƉƵůƐŝŶŐƚŚĞŵǁŝƚŚĂŶƟŐĞŶĂŶĚĂĚũƵǀĂŶƚƐex

vivo͕ ĂŶĚ ƌĞŝŶũĞĐƟŶŐ ƚŚĞŵ57_{͘ dŚĞƐĞ Ɛ ĐĂŶ ƚŚĞŶ ƉƌĞƐĞŶƚ ƚŚĞ ƚƵŵŽƌͲƐƉĞĐŝĮĐ ĞƉŝƚŽƉĞƐ}

to T cells and prime them to destroy the cancer cells58_{͘dŽďŽŽƐƚϴ}+_{T cell responses,}

ŵŝĐĞǁĞƌĞŝŶũĞĐƚĞĚĂŌĞƌƐŽŵĞƟŵĞǁŝƚŚĂŵŝǆŽĨĂŶĂŐŽŶŝƐƟĐĂŶƟͲϰϬĂŶƟďŽĚǇ;ŽͿ͕ ĂŶƟŐĞŶ ;Ϳ ĂŶĚ Ă ƚŽůůͲůŝŬĞ ƌĞĐĞƉƚŽƌ ;d>ZͿ ůŝŐĂŶĚ ;dͿ WŽůǇ /͗59_{. Unfortunately, ex vivo}

ƉƌŝŵŝŶŐ ŽĨ Ɛ ŝƐ ǀĞƌǇ ůĂďŽƌͲŝŶƚĞŶƐŝǀĞ ĂŶĚ ĞǆƉĞŶƐŝǀĞ͕ ƉƌŽŚŝďŝƟŶŐ ǁŝĚĞͲƐƉƌĞĂĚ ƵƐĞ57_.

tĞƉƌŽƉŽƐĞ^W͗WdW͗,K>ůŝƉŽƐŽŵĞƐĂƐĂĚĞůŝǀĞƌǇƐǇƐƚĞŵƚŽĚĞůŝǀĞƌƚŚĞĂŶƟŐĞŶƚŽ Ɛin situ in a simpler way60_{. First, we compared non-adjuvanted Adpgk}

mut liposomes

(7)

^d/E'ĂŐŽŶŝƐƚĐĚŝ'DW͘DŝĐĞǁĞƌĞƉƌŝŵĞĚǁŝƚŚůŝƉŽƐŽŵĞƐĂŶĚďŽŽƐƚĞĚǁŝƚŚŽd͘dŚĞ ĐĚŝ'DWůŝƉŽƐŽŵĞƐŝŶĚƵĐĞĚƚŚĞƐƚƌŽŶŐĞƐƚĂŶƟŐĞŶͲƐƉĞĐŝĮĐϴ+_{T cell response, so we}

ĐŽŶƟŶƵĞĚǁŝƚŚƚŚŝƐĨŽƌŵƵůĂƟŽŶŝŶĨƵƌƚŚĞƌĞǆƉĞƌŝŵĞŶƚƐ͘/ŶĂĚŝƌĞĐƚĐŽŵƉĂƌŝƐŽŶ͕ĐĚŝ'DW ůŝƉŽƐŽŵĞƐƉĞƌĨŽƌŵĞĚĂƐŐŽŽĚĂƐͲŽdǀĂĐĐŝŶĂƟŽŶ͘tĞĂůƐŽƚĞƐƚĞĚƚŚĞƐƵŝƚĂďŝůŝƚǇŽĨ the liposomes with another neoepitope, Alg8_mut. Similar to Adpgk_mut͕ĞŶĐĂƉƐƵůĂƟŽŶŽĨ ƚŚĞĂŶƟŐĞŶŝŶĐĚŝ'DWůŝƉŽƐŽŵĞƐŐƌĞĂƚůǇďŽŽƐƚĞĚƚŚĞŝŵŵƵŶĞƌĞƐƉŽŶƐĞĂŶĚůĞĚƚŽǀĞƌǇ ůŽŶŐͲůĂƐƟŶŐƌĞƐƉŽŶƐĞƐǁŚŝĐŚǁĞƌĞƐŝŵŝůĂƌƚŽƚŚŽƐĞĂĐŚŝĞǀĞĚǁŝƚŚͲŽd56_{͘EĞǆƚ͕ǁĞ} ĂŝŵĞĚƚŽŝŵƉƌŽǀĞŽƵƌǀĂĐĐŝŶĂƟŽŶƉƌŽƚŽĐŽůďǇĞůŝĐŝƟŶŐϰ+_{dĐĞůůŚĞůƉǁŝƚŚƚŚĞϰ}+ epitope MTAG85B61_{ĂŶĚƐĞůĞĐƟŶŐĂůŽŶŐǀĞƌƐŝŽŶŽĨĚƉŐŬ} mutƉĞƉƟĚĞ 62_{͘dŚĞůŽŶŐƉĞƉƟĚĞ} ĚŝĚŶŽƚĞŶŚĂŶĐĞƚŚĞϴ+_{dĐĞůůƌĞƐƉŽŶƐĞĂŐĂŝŶƐƚƚŚĞŵŝŶŝŵĂůĞƉŝƚŽƉĞ͘tĞĂůƐŽƐĂǁŶŽ} ĞǀŝĚĞŶĐĞŽĨƚŚĞDd'ϴϱͲŝŶĚƵĐĞĚϰ+_{dĐĞůůĂĐƟǀĂƟŽŶďŽŽƐƟŶŐƚŚĞϴ}+_responses.

Due to the lack of improvement of the Adpgk_mutƌĞƐƉŽŶƐĞƐǁŝƚŚƚŚĞĂĚĚŝƟŽŶŽĨĂϰ+

dĐĞůůĞƉŝƚŽƉĞŽƌĂůŽŶŐƉĞƉƟĚĞ͕ǁĞĚĞĐŝĚĞĚƚŽƉĞƌĨŽƌŵĂƚƵŵŽƌƐƚƵĚǇƵƐŝŶŐŽŶůǇƚŚĞ minimal Adpgk_mut ƉĞƉƟĚĞ ŝŶ ĐĚŝ'DW ůŝƉŽƐŽŵĞƐ͘ ,ĞƌĞ͕ ǁĞ ŽďƐĞƌǀĞĚ ĞǆƚƌĞŵĞůǇ ŚŝŐŚ ĂŶƟŐĞŶͲƐƉĞĐŝĮĐƌĞƐƉŽŶƐĞƐƚŽƚŚĞĂŶƟŐĞŶ;ƵƉƚŽϲϬйŽĨĂůůϴ+_{T cells responded to the}

ĂŶƟŐĞŶďǇƉƌŽĚƵĐŝŶŐ /&EɶͿ͘tĞŽďƐĞƌǀĞĚƚƵŵŽƌƌĞŐƌĞƐƐŝŽŶǁŝƚŚŝŶϯϬĚĂǇƐĂŶĚϭϬϬй ƐƵƌǀŝǀĂůŝŶŵŝĐĞƌĞĐĞŝǀŝŶŐƚŚĞ>^ͲŽdǀĂĐĐŝŶĂƟŽŶ͘KǀĞƌĂůů͕ƚŚŝƐǁŽƌŬƐŚŽǁƐƚŚĂƚĐĚŝ'DW ůŝƉŽƐŽŵĞƐĂƌĞĂǀĞƌǇƉŽǁĞƌĨƵůƉůĂƞŽƌŵĨŽƌĞŶĐĂƉƐƵůĂƟŶŐƚƵŵŽƌŶĞŽĞƉŝƚŽƉĞƐƚŽŝŶĚƵĐĞ ƐƚƌŽŶŐĂŶƟŐĞŶͲƐƉĞĐŝĮĐϴ+_{T cells and eliminate established tumors.}

WĞƌƐƉĞĐƟǀĞƐ tŚŝůĞǁĞƉƌĞƐĞŶƚĞĚƐĞǀĞƌĂůĚŝīĞƌĞŶƚƚƌĞĂƚŵĞŶƚƐƚƌĂƚĞŐŝĞƐĨŽƌĚŝīĞƌĞŶƚĚŝƐĞĂƐĞƐ͕ ůŝƉŽƐŽŵĞƐǁĞƌĞƵƐĞĚŝŶĂůůĐĂƐĞƐ͘tĞƵƐĞĚůŝƉŽƐŽŵĞƐƚŽĚĞůŝǀĞƌĂĚƌƵŐƚŽƉůĂƋƵĞͲƌĞƐŝĚĞŶƚ ŵĂĐƌŽƉŚĂŐĞƐďǇƵƐŝŶŐĂƚĂƌŐĞƚĞĚĂƉƉƌŽĂĐŚ͘tĞĂůƐŽŵĂŶŝƉƵůĂƚĞĚƚŚĞƉŚǇƐŝĐŽĐŚĞŵŝĐĂů ƉƌŽƉĞƌƟĞƐ ŽĨ ůŝƉŽƐŽŵĞƐ ƚŽ ŝŶĚƵĐĞ ĂŶƟͲŝŶŇĂŵŵĂƚŽƌǇ Žƌ ƉƌŽͲŝŶŇĂŵŵĂƚŽƌǇ d ĐĞůů ƌĞƐƉŽŶƐĞƐ͘ dŚĞƐĞ ƐƚƵĚŝĞƐ ĨƵƌƚŚĞƌ ĂĚĚ ƚŽ ƚŚĞ ĞǀŝĚĞŶĐĞ ƚŚĂƚ ůŝƉŽƐŽŵĞƐ ĂƌĞ ĞǆƚƌĞŵĞůǇ ǀĞƌƐĂƟůĞĚƌƵŐĚĞůŝǀĞƌǇƉĂƌƟĐůĞƐ63_. In ĐŚĂƉƚĞƌ ϱ ǁĞ ĞǆƉůŽƌĞĚ Ă ŵĞƚŚŽĚ ĨŽƌ ƚƌĞĂƟŶŐ ĂƚŚĞƌŽƐĐůĞƌŽƐŝƐ ďǇ ƵƐŝŶŐ ƚĂƌŐĞƚĞĚ ůŝƉŽƐŽŵĞƐƚŽĚĞůŝǀĞƌĂĚƌƵŐ͘ƐŝĚĞĨƌŽŵƚĂƌŐĞƟŶŐƚŽĂƚŚĞƌŽƐĐůĞƌŽƟĐƉůĂƋƵĞƐ͕ƚĂƌŐĞƚĞĚ liposomes have been applied in the treatment of cancer64_{, and to cross the}

blood-brain barrier to treat neurological diseases such as Alzheimer’s65_{. Several liposomal}

ĨŽƌŵƵůĂƟŽŶƐ͕ŝŶĐůƵĚŝŶŐW'ǇůĂƚĞĚůŝƉŽƐŽŵĞƐ͕ŚĂǀĞĂůƌĞĂĚǇďĞĞŶƐŚŽǁŶƚŽďĞƐĂĨĞĂŶĚ ĂƌĞ & ĂŶĚ D ĂƉƉƌŽǀĞĚ66_{͘ &ƵƌƚŚĞƌŵŽƌĞ͕ W'ǇůĂƚĞĚ ůŝƉŽƐŽŵĞƐ ŚĂǀĞ ďĞĞŶ ƵƐĞĚ ƚŽ} ƉĂƐƐŝǀĞůǇĚĞůŝǀĞƌƉƌĞĚŶŝƐŽůŽŶĞ;ĂŶĂŶƟͲŝŶŇĂŵŵĂƚŽƌǇĚƌƵŐͿƚŽĂƚŚĞƌŽƐĐůĞƌŽƟĐƉůĂƋƵĞƐŝŶ ŚƵŵĂŶƐ͕ŝŶĚŝĐĂƟŶŐƚŚĂƚƚŚĞƌĞŝƐƐŽŵĞƚƌĂŶƐůĂƟŽŶĨƌŽŵĂŶŝŵĂůƐƚŽŚƵŵĂŶƐ67_. tĞŚĂǀĞĞŵƉŚĂƐŝǌĞĚƚŚĞŝŵƉŽƌƚĂŶĐĞŽĨĚĞƐŝŐŶŝŶŐůŝƉŽƐŽŵĞƐǁŝƚŚƐƉĞĐŝĮĐƉŚǇƐŝĐŽĐŚĞŵŝĐĂů ƉĂƌĂŵĞƚĞƌƐ͕ ĂŶĚ ƐƵŵŵĂƌŝǌĞĚ ƚŚĞ ƐŝŐŶŝĮĐĂŶĐĞ ŽĨ ƐŝǌĞ͕ ƐŚĂƉĞ ĂŶĚ ƌŝŐŝĚŝƚǇ ŝŶ ĐŚĂƉƚĞƌ Ϯ͘ >ŝƉŽƐŽŵĂů ƌŝŐŝĚŝƚǇ ǁĂƐ ŝŶƚƌŝŐƵŝŶŐ ƐŝŶĐĞ ǁĞ ĐŽƵůĚ ŶŽƚ ĮŶĚ Ă ƐƵďƐƚĂŶƟĂů ĂŵŽƵŶƚ ŽĨ

literature concerning this parameter. Therefore, we aimed to enhance our understanding ŽĨƚŚŝƐƉĂƌĂŵĞƚĞƌĂŶĚƉĞƌĨŽƌŵĞĚĂĚĞƚĂŝůĞĚƐƚƵĚǇĞǆĂŵŝŶŝŶŐƚŚĞƌĞůĂƟŽŶƐŚŝƉďĞƚǁĞĞŶ liposomal rigidity and Treg responses in ĐŚĂƉƚĞƌϯ͘&ŽƌƚŚŝƐ͕ǁĞƉƌĞƐĞŶƚĞĚĂŶŽƉƟŵŝǌĞĚ

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7

ǁŚĞƚŚĞƌƚŚĞŝŵŵƵŶĞĞīĞĐƚƐǁĞŽďƐĞƌǀĞĚĂƉƉůǇƚŽĂǁŝĚĞƌƌĂŶŐĞŽĨƌŝŐŝĚŝƟĞƐ͘dŚĞĞǆĂĐƚ ŵĞĐŚĂŶŝƐŵŽĨǁŚǇƌŝŐŝĚŝƚǇĂīĞĐƚƐƚŚĞŝŵŵƵŶĞƌĞƐƉŽŶƐĞŝƐƐƟůůŶŽƚĨƵůůǇƵŶĚĞƌƐƚŽŽĚ͕ĂŶĚ ĨƵƚƵƌĞƐƚƵĚŝĞƐĞǆĂŵŝŶŝŶŐƚŚŝƐŝŶŵŽƌĞĚĞƚĂŝůǁŽƵůĚďĞǀĞƌǇǀĂůƵĂďůĞ͘ dŚĞ ŝŶĚƵĐƟŽŶ ŽĨ ĂŶƟŐĞŶͲƐƉĞĐŝĮĐ dƌĞŐƐ ĂƌĞ Ă ĨŽĐƵƐ ŽĨ ĐŚĂƉƚĞƌƐ ϯ and ϰ͘ tĞ ŝĚĞŶƟĮĞĚĂƉĞƉƟĚĞĚĞƌŝǀĞĚĨƌŽŵŵƵƌŝŶĞƉŽϭϬϬĨŽƌǀĂĐĐŝŶĂƟŽŶ͕ďƵƚŚƵŵĂŶƉŽϭϬϬ ĞƉŝƚŽƉĞƐ ŚĂǀĞ ďĞĞŶ ŝĚĞŶƟĮĞĚ ǁŚŝĐŚ ǁĞƌĞ ƐƵĐĐĞƐƐĨƵů Ăƚ ƌĞĚƵĐŝŶŐ ĂƚŚĞƌŽƐĐůĞƌŽƐŝƐ ŝŶ humanized mice68_{͘dŚĞƐĞƉĞƉƟĚĞƐĐĂŶďĞĞŶĐĂƉƐƵůĂƚĞĚŝŶůŝƉŽƐŽŵĞƐƚŽĞŶŚĂŶĐĞƚŚĞŝƌ} ĞīĞĐƚƐĂŶĚƐĂĨĞƚǇ͘hŶĨŽƌƚƵŶĂƚĞůǇ͕ƐŽĨĂƌ͕ŶŽĐůŝŶŝĐĂůƐƚƵĚŝĞƐŚĂǀĞďĞĞŶƉĞƌĨŽƌŵĞĚƵƐŝŶŐ ƉŽϭϬϬͲĚĞƌŝǀĞĚ ĞƉŝƚŽƉĞƐ͕ ƐŽ ƚŚĞƌĞ ŝƐ ƐƟůů Ă ƋƵĞƐƟŽŶ ĂďŽƵƚ ƚŚĞ ƚƌĂŶƐůĂƟŽŶ ŽĨ ƚŚĞƐĞ ƐƚƵĚŝĞƐ ƚŽ Ă ĐůŝŶŝĐĂů ƐĞƫŶŐ69_{͘ ^ŝŶĐĞ ŵĂŶǇ ƉĞŽƉůĞ ƐƵīĞƌŝŶŐ ĨƌŽŵ ĂƚŚĞƌŽƐĐůĞƌŽƐŝƐ ƵƐĞ} ƐƚĂƟŶƐ ƚŽ ĐŽŶƚƌŽů ƚŚĞŝƌ ĚŝƐĞĂƐĞ͕ ƚŚĞ ŝŶƚĞƌĂĐƟŽŶ ďĞƚǁĞĞŶ ƐƚĂƟŶƐ ĂŶĚ ƉĞƉƟĚĞƐ ĂŶĚͬŽƌ ůŝƉŽƐŽŵĞƐŶĞĞĚƐƚŽďĞƐƚƵĚŝĞĚĂƐǁĞůů͘&ŽƌŝŶƐƚĂŶĐĞ͕ĐŽŵďŝŶĞĚƵƐĞŽĨƐƚĂƟŶƐĂŶĚ>>Ͳ mimicking liposomes led to the liposomes crossing the blood-brain barrier in an in vitro culture model70_{͕ǁŚŝĐŚĐŽƵůĚďĞĚĂŶŐĞƌŽƵƐ͘&ƵƌƚŚĞƌŵŽƌĞ͕ƵƐŝŶŐŇƵŽƌĞƐĐĞŶĐĞĂŶŝƐŽƚƌŽƉǇ͕}

ŝƚŚĂƐďĞĞŶƐŚŽǁŶƚŚĂƚƐŽŵĞƐƚĂƟŶƐŝŶƚĞƌĂĐƚǁŝƚŚƚŚĞďŝůĂǇĞƌŽĨůŝƉŽƐŽŵĞƐĂŶĚĐĂŶĂůƚĞƌ ƚŚĞŝƌŇƵŝĚŝƚǇ71_{, and thereby their immunogenicity. As opposed to our study with Lyp-1}

liposomes, the tolerogenic liposomes in ĐŚĂƉƚĞƌϰǁĞƌĞĂĚŵŝŶŝƐƚĞƌĞĚĂƚƚŚĞƐĂŵĞƟŵĞ

ĂƐƐƚĂƌƟŶŐƚŚĞǁĞƐƚĞƌŶͲƚǇƉĞĚŝĞƚ͖ŝƚǁŽƵůĚďĞŵŽƌĞĐůŝŶŝĐĂůůǇƌĞůĞǀĂŶƚƚŽĂĚŵŝŶŝƐƚĞƌƚŚĞ liposomes in mice with established atherosclerosis.

Tregs are not only important in the treatment of atherosclerosis, but are involved in many other diseases, grouped under the term autoimmune diseases72_͘tĞ

ĨŽƵŶĚĂƌŽůĞĨŽƌƐĞƌƵŵͲĚĞƌŝǀĞĚϭƋŝŶƚŚĞŝŶƚĞƌĂĐƟŽŶŽĨůŝƉŽƐŽŵĞƐĂŶĚ^ZƐ͕ĂŶĚŝƚǁŽƵůĚ ďĞ ŝŶƚĞƌĞƐƟŶŐ ƚŽ ƐƚƵĚǇ ƚŚŝƐ ŵĞĐŚĂŶŝƐŵ ŝŶ ŵŽƌĞ ĚĞƚĂŝů͘ ƵƚŽŝŵŵƵŶĞ ĚŝƐĞĂƐĞƐ ŝŶĐůƵĚĞ ĚŝƐĞĂƐĞƐƐƵĐŚĂƐƌŽŚŶ͛ƐĚŝƐĞĂƐĞƐ͕ĚŝĂďĞƚĞƐ͕ŵƵůƟƉůĞƐĐůĞƌŽƐŝƐĂŶĚƌŚĞƵŵĂƚŽŝĚĂƌƚŚƌŝƟƐ͕ ĂŶĚĂīĞĐƚĂŶĞƐƟŵĂƚĞĚϳ͘ϲʹϵ͘ϰйŽĨƚŚĞƉŽƉƵůĂƟŽŶ͕ǁŝƚŚǁŽŵĞŶďĞŝŶŐĂƚĂŚŝŐŚĞƌƌŝƐŬ73_.

There is currently no cure for any of the autoimmune diseases, and treatment focuses ŽŶƐǇƐƚĞŵŝĐƐƵƉƉƌĞƐƐŝŽŶŽĨŝŶŇĂŵŵĂƟŽŶǁŝƚŚĂŶƟͲŝŶŇĂŵŵĂƚŽƌǇĚƌƵŐƐ͘,ŽǁĞǀĞƌ͕ƚŚĞƐĞ ƚŚĞƌĂƉŝĞƐĐĂŶƌĞƐƵůƚŝŶƐĞǀĞƌĞƐŝĚĞĞīĞĐƚƐĂŶĚƐƵƐĐĞƉƟďŝůŝƚǇƚŽŝŶĨĞĐƟŽŶ͕ĞƐƉĞĐŝĂůůǇƵƉŽŶ long-term treatment74-76_{͕ĞŵƉŚĂƐŝǌŝŶŐƚŚĞŶĞĞĚĨŽƌŵŽƌĞƐƉĞĐŝĮĐƚŚĞƌĂƉŝĞƐ͘tŚŝůĞǁĞ}

ŚĂǀĞŽŶůǇƐƚƵĚŝĞĚƚŚĞĞīĞĐƚƐŽĨdƌĞŐͲŝŶĚƵĐŝŶŐůŝƉŽƐŽŵĞƐŽŶĂƚŚĞƌŽƐĐůĞƌŽƐŝƐ͕ŽƚŚĞƌƐƚƵĚŝĞƐ ŚĂǀĞ ďĞĞŶ ƉĞƌĨŽƌŵĞĚ ǁŝƚŚ ƚŽůĞƌŽŐĞŶŝĐ ůŝƉŽƐŽŵĞƐ ƚƌĞĂƟŶŐ ĚŝĂďĞƚĞƐ33_{and rheumatoid}

ĂƌƚŚƌŝƟƐ77_{. All of this work is vital for developing a possible treatment for autoimmune}

diseases.

/ŵŵƵŶŽŵŽĚƵůĂƟŽŶ ǁĂƐ ĂůƐŽ ƚŚĞ ĨŽĐƵƐ ŽĨ ĐŚĂƉƚĞƌ ϲ, but instead of suppressing ƚŚĞ ŝŵŵƵŶĞ ƌĞƐƉŽŶƐĞ ƚŽ ĂŶ ĂŶƟŐĞŶ͕ ǁĞ ĂŝŵĞĚ ƚŽ ĞŶŚĂŶĐĞ ŝƚ ďǇ ƚŚĞ ƵƐĞ ŽĨ ĐĂƟŽŶŝĐ ůŝƉŽƐŽŵĞƐ͘ ĂŶĐĞƌ ŝŵŵƵŶŽƚŚĞƌĂƉǇ ǀŝĂ Ɛ78_{or T cells}79_{, and immunotherapy against}

ŶĞŽĂŶƟŐĞŶƐ80_{ŚĂƐ ďĞĞŶ ƐƚƵĚŝĞĚ ĨŽƌ ƐĞǀĞƌĂů ǇĞĂƌƐ͘ tĞ ĂƌŐƵĞ ƚŚĂƚ ŝŵŵƵŶŽƚŚĞƌĂƉǇ ǀŝĂ} ůŝƉŽƐŽŵĞƐ ŝƐ Ă ĨĂƐƚĞƌ͕ ŵŽƌĞ ĐŽƐƚͲĞīĞĐƟǀĞ ƚƌĞĂƚŵĞŶƚ ƐƚƌĂƚĞŐǇ͘ /ŶĚĞĞĚ͕ ŶĂŶŽƉĂƌƟĐůĞƐ͕ ŝŶĐůƵĚŝŶŐ ůŝƉŽƐŽŵĞƐ͕ ŚĂǀĞ ďĞĞŶ ƐŚŽǁŶ ƚŽ ďĞ ĞīĞĐƟǀĞ ŝŶ ĐĂŶĐĞƌ ƚŚĞƌĂƉǇ81_{, and our} ǁŽƌŬ ĐŽŶƚƌŝďƵƚĞƐ ƚŽ ƚŚŝƐ ĞǀŝĚĞŶĐĞ͘ dŽŽůƐ ƚŽ ŝĚĞŶƟĨǇ ĂŶƟŐĞŶƐ ƐƉĞĐŝĮĐ ƚŽ ĂƵƚŽŝŵŵƵŶĞ diseases82,83_{͕ ŝŶĐůƵĚŝŶŐ ƚŚĞ ĂƚŚĞƌŽƐĐůĞƌŽƐŝƐ ĂŶƟŐĞŶ ƉϯϱϬϬ ŝĚĞŶƟĮĞĚ ŝŶ ƚŚŝƐ ƚŚĞƐŝƐ͕ ĂŶĚ} cancer84_{ĂƌĞŝŵƉƌŽǀŝŶŐ͘ŽŵďŝŶĞĚǁŝƚŚƚŚĞĂďŝůŝƚǇŽĨůŝƉŽƐŽŵĞƐƚŽĞŶĐĂƉƐƵůĂƚĞĂǁŝĚĞ}

range of epitopes, liposomes could be an important player in the future of personalized therapies85_{͘/ƚƐŚŽƵůĚďĞŶŽƚĞĚƚŚĂƚ͕ǁŚŝůĞǁĞŽďƐĞƌǀĞĚŶŽƚŽǆŝĐŝƚǇŝŶŽƵƌĂŶŝŵĂůƐƚƵĚŝĞƐ͕}

Ăƚ ŚŝŐŚ ĚŽƐĞƐ ĐĂƟŽŶŝĐ ƉŚŽƐƉŚŽůŝƉŝĚƐ ŝŶĚƵĐĞ ƚŽǆŝĐŝƚǇ ŝŶ in vivo animal models86_{and in}

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ƐƚƌŝǀĞĨŽƌŵŝŶŝŵŝǌŝŶŐƚŚĞĚŽƐĞŽĨƚŚĞĐĂƟŽŶŝĐƉŚŽƐƉŚŽůŝƉŝĚƐŝŶƚŚĞůŝƉŽƐŽŵĞƐ͘/ŶŽƌĚĞƌƚŽ ƉƌŽŐƌĞƐƐƚŽĐůŝŶŝĐĂůƚƌŝĂůƐ͕ŵŽƌĞƚŽǆŝĐŝƚǇƐƚƵĚŝĞƐŶĞĞĚƚŽďĞƉĞƌĨŽƌŵĞĚŝŶĂŶŝŵĂůŵŽĚĞůƐ to test whether the liposomes are safe to use, either in the short-term or long-term. ƐŝĚĞĨƌŽŵƚŚĞŶĞĞĚƚŽƚĞƐƚƚŚĞƐĂĨĞƚǇŽĨƚŚĞůŝƉŽƐŽŵĞƐĨŽƌĐůŝŶŝĐĂůƵƐĞ͕ƚĞƐƟŶŐ ŝŶŚƵŵĂŶƐƌĞƋƵŝƌĞƐůĂƌŐĞĂŵŽƵŶƚƐŽĨůŝƉŽƐŽŵĞƐĂŶĚƚŚĞĞŶĐĂƉƐƵůĂƚĞĚĐŽŶƚĞŶƚƐ;ĚƌƵŐ͕ ƉĞƉƟĚĞ͕ĂĚũƵǀĂŶƚͿ͘^ĐĂůĞͲƵƉŝƐŶŽƚŽŶůǇƉŽƚĞŶƟĂůůǇǀĞƌǇĐŽƐƚůǇ;ĂůƚŚŽƵŐŚĞŶĐĂƉƐƵůĂƟŽŶ ŽĨĂĐŽŵƉŽƵŶĚŝŶĂ;ƚĂƌŐĞƚĞĚͿŶĂŶŽƉĂƌƟĐůĞ ŐƌĞĂƚůǇĚĞĐƌĞĂƐĞƐƚŚĞƌĞƋƵŝƌĞĚĚŽƐĞ͕ĂŶĚ therefore cost88_{Ϳ͕ ďƵƚ ŝƚ ĐĂŶ ĂůƚĞƌ ƚŚĞ ůŝƉŽƐŽŵĞƐ͛ ƉŚǇƐŝĐŽĐŚĞŵŝĐĂů ƉƌŽƉĞƌƟĞƐ͘ dŚŝƐ ŝƐ} ĂůƐŽƚƌƵĞĨŽƌƚŚĞ'DWƉƌŽĚƵĐƟŽŶŽĨůŝƉŽƐŽŵĞƐ͘DĞƚŚŽĚƐƐƵĐŚĂƐŵŝĐƌŽͲŇƵŝĚŝĐƐ89_and

ĞƚŚĂŶŽůŝŶũĞĐƟŽŶ90,91_{are proven to be able to reproducibly manufacture large amounts}

ŽĨ ůŝƉŽƐŽŵĞƐ ƵŶĚĞƌ 'DW ĐŽŶĚŝƟŽŶƐ͘ ,ŽǁĞǀĞƌ͕ Ă ĚĞƚĂŝůĞĚ ĞǀĂůƵĂƟŽŶ ŽĨ ƚŚĞ ĞīĞĐƚ ŽĨ ƉƌŽĚƵĐƟŽŶŵĞƚŚŽĚŽŶůŝƉŽƐŽŵĂůƉƌŽƉĞƌƟĞƐƐŚŽƵůĚďĞƉĞƌĨŽƌŵĞĚ͘ĞƐƉŝƚĞƚŚŝƐ͕ƚŚĞƌĞ ĂƌĞ Ă ƐƵďƐƚĂŶƟĂů ŶƵŵďĞƌ ŽĨ ůŝƉŽƐŽŵĞƐ ƚŚĂƚ ĂƌĞ ĂůƌĞĂĚǇ ĂƉƉƌŽǀĞĚ ĨŽƌ ŚƵŵĂŶƐ͕ Žƌ ŝŶ clinical trials66_{͕ƐŽƚŚĞƉŽƚĞŶƟĂůĨŽƌĨƵƌƚŚĞƌĚĞǀĞůŽƉŝŶŐƚŚĞƚƌĞĂƚŵĞŶƚƐƉƌĞƐĞŶƚĞĚŚĞƌĞŝƐ}

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7

ZĞĨĞƌĞŶĐĞƐ

ϭ ůĞŵĞŶƚĞͲĂƐĂƌĞƐ͕y͘ et al.ǆƉĂŶĚŝŶŐĂŶƟŐĞŶͲƐƉĞĐŝĮĐƌĞŐƵůĂƚŽƌǇŶĞƚǁŽƌŬƐƚŽ treat autoimmunity. Nature ϱϯϬ͕ϰϯϰͲϰϰϬ͕ĚŽŝ͗ϭϬ͘ϭϬϯϴͬŶĂƚƵƌĞϭϲϵϲϮ;ϮϬϭϲͿ͘

Ϯ &ŽŬƐ͕͕͘͘>ŝĐŚƚŵĂŶ͕͘,͘Θ<ƵŝƉĞƌ͕:͘dƌĞĂƟŶŐĂƚŚĞƌŽƐĐůĞƌŽƐŝƐǁŝƚŚ regulatory T cells. Arterioscler Thromb Vasc Biol ϯϱ͕ϮϴϬͲϮϴϳ͕ĚŽŝ͗ϭϬ͘ϭϭϲϭͬ

ds,͘ϭϭϰ͘ϯϬϯϱϲϴ;ϮϬϭϱͿ͘

ϯ ǀĂŶ,ĞƌǁŝũŶĞŶ͕D͘:͘ et al.ZĞŐƵůĂƚŽƌǇdĐĞůůƐƚŚĂƚƌĞĐŽŐŶŝǌĞĂƵďŝƋƵŝƚŽƵƐƐƚƌĞƐƐͲ ŝŶĚƵĐŝďůĞƐĞůĨͲĂŶƟŐĞŶĂƌĞůŽŶŐͲůŝǀĞĚƐƵƉƉƌĞƐƐŽƌƐŽĨĂƵƚŽŝŵŵƵŶĞĂƌƚŚƌŝƟƐ͘Proc

Natl Acad Sci U S A ϭϬϵ͕ϭϰϭϯϰͲϭϰϭϯϵ͕ĚŽŝ͗ϭϬ͘ϭϬϳϯͬƉŶĂƐ͘ϭϮϬϲϴϬϯϭϬϵ;ϮϬϭϮͿ͘

ϰ 'ƌŝǀĞŶŶŝŬŽǀ͕^͘/͕͘'ƌĞƚĞŶ͕&͘Z͘Θ<ĂƌŝŶ͕D͘/ŵŵƵŶŝƚǇ͕ŝŶŇĂŵŵĂƟŽŶ͕ĂŶĚĐĂŶĐĞƌ͘

Cell ϭϰϬ͕ϴϴϯͲϴϵϵ͕ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘ĐĞůů͘ϮϬϭϬ͘Ϭϭ͘ϬϮϱ;ϮϬϭϬͿ͘

ϱ ŽƵůŝĞ͕W͘'͕͘sĂŶĚĞŶǇŶĚĞ͕͘:͕͘ǀĂŶĚĞƌƌƵŐŐĞŶ͕W͘ΘŽŽŶ͕d͘dƵŵŽƵƌ ĂŶƟŐĞŶƐƌĞĐŽŐŶŝǌĞĚďǇdůǇŵƉŚŽĐǇƚĞƐ͗ĂƚƚŚĞĐŽƌĞŽĨĐĂŶĐĞƌŝŵŵƵŶŽƚŚĞƌĂƉǇ͘

Nat Rev Cancer ϭϰ͕ϭϯϱͲϭϰϲ͕ĚŽŝ͗ϭϬ͘ϭϬϯϴͬŶƌĐϯϲϳϬ;ϮϬϭϰͿ͘

ϲ ZĂƉŚĂĞů͕/͕͘EĂůĂǁĂĚĞ͕^͕͘ĂŐĂƌ͕d͘E͘Θ&ŽƌƐƚŚƵďĞƌ͕d͘'͘dĐĞůůƐƵďƐĞƚƐĂŶĚƚŚĞŝƌ ƐŝŐŶĂƚƵƌĞĐǇƚŽŬŝŶĞƐŝŶĂƵƚŽŝŵŵƵŶĞĂŶĚŝŶŇĂŵŵĂƚŽƌǇĚŝƐĞĂƐĞƐ͘Cytokine ϳϰ, ϱͲϭϳ͕ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘ĐǇƚŽ͘ϮϬϭϰ͘Ϭϵ͘Ϭϭϭ;ϮϬϭϱͿ͘ ϳ EĂƌĂŶ͕<͕͘EƵŶĚĂůĂůů͕d͕͘ŚĞƩǇ͕^͘ΘĂƌƚŚ͕^͘WƌŝŶĐŝƉůĞƐŽĨ/ŵŵƵŶŽƚŚĞƌĂƉǇ͗ /ŵƉůŝĐĂƟŽŶƐĨŽƌdƌĞĂƚŵĞŶƚ^ƚƌĂƚĞŐŝĞƐŝŶĂŶĐĞƌĂŶĚ/ŶĨĞĐƟŽƵƐŝƐĞĂƐĞƐ͘Front Microbiol ϵ͕ϯϭϱϴ͕ĚŽŝ͗ϭϬ͘ϯϯϴϵͬĨŵŝĐď͘ϮϬϭϴ͘Ϭϯϭϱϴ;ϮϬϭϴͿ͘ ϴ &ĞůĚŵĂŶŶ͕D͘Θ^ƚĞŝŶŵĂŶ͕>͘ĞƐŝŐŶŽĨĞīĞĐƟǀĞŝŵŵƵŶŽƚŚĞƌĂƉǇĨŽƌŚƵŵĂŶ autoimmunity. Nature ϰϯϱ͕ϲϭϮͲϲϭϵ͕ĚŽŝ͗ϭϬ͘ϭϬϯϴͬŶĂƚƵƌĞϬϯϳϮϳ;ϮϬϬϱͿ͘ ϵ DĂƚƐŝŶŐŽƵ͕͘ΘĞŵĞƚǌŽƐ͕͘ĂůŽƌŝŵĞƚƌŝĐƐƚƵĚǇŽŶƚŚĞŝŶĚƵĐƟŽŶŽĨ ŝŶƚĞƌĚŝŐŝƚĂƚĞĚƉŚĂƐĞŝŶŚǇĚƌĂƚĞĚWWďŝůĂǇĞƌƐďǇďŝŽĂĐƟǀĞůĂďĚĂŶĞƐĂŶĚ ĐŽƌƌĞůĂƟŽŶƚŽƚŚĞŝƌůŝƉŽƐŽŵĞƐƚĂďŝůŝƚǇ͗dŚĞƌŽůĞŽĨĐŚĞŵŝĐĂůƐƚƌƵĐƚƵƌĞ͘Chem Phys Lipids ϭϰϱ͕ϰϱͲϲϮ͕ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘ĐŚĞŵƉŚǇƐůŝƉ͘ϮϬϬϲ͘ϭϬ͘ϬϬϰ;ϮϬϬϳͿ͘ ϭϬ ůƚƵŶĂǇĂƌ͕͕͘^ĂŚŝŶ͕/͘Θ<ĂǌĂŶĐŝ͕E͘ĐŽŵƉĂƌĂƟǀĞƐƚƵĚǇŽĨƚŚĞĞīĞĐƚƐŽĨ ĐŚŽůĞƐƚĞƌŽůĂŶĚĚĞƐŵŽƐƚĞƌŽůŽŶǌǁŝƩĞƌŝŽŶŝĐWWŵŽĚĞůŵĞŵďƌĂŶĞƐ͘Chem Phys Lipids ϭϴϴ͕ϯϳͲϰϱ͕ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘ĐŚĞŵƉŚǇƐůŝƉ͘ϮϬϭϱ͘Ϭϯ͘ϬϬϲ;ϮϬϭϱͿ͘ ϭϭ dĂŬĞĐŚŝͲ,ĂƌĂǇĂ͕z͕͘^ĂŬĂŝͲ<ĂƚŽ͕<͘Θ'ŽĚĂ͕z͘DĞŵďƌĂŶĞZŝŐŝĚŝƚǇĞƚĞƌŵŝŶĞĚ ďǇƚŽŵŝĐ&ŽƌĐĞDŝĐƌŽƐĐŽƉǇ/ƐĂWĂƌĂŵĞƚĞƌŽĨƚŚĞWĞƌŵĞĂďŝůŝƚǇŽĨ>ŝƉŽƐŽŵĂů DĞŵďƌĂŶĞƐƚŽƚŚĞ,ǇĚƌŽƉŚŝůŝĐŽŵƉŽƵŶĚĂůĐĞŝŶ͘AAPS PharmSciTech ϭϴ, ϭϴϴϳͲϭϴϵϯ͕ĚŽŝ͗ϭϬ͘ϭϮϬϴͬƐϭϮϮϰϵͲϬϭϲͲϬϲϮϰͲǆ;ϮϬϭϳͿ͘ ϭϮ ŚĂŽ͕>͕͘&ĞŶŐ͕^͘^͕͘<ŽĐŚĞƌŐŝŶƐŬǇ͕E͘Θ<ŽƐƚĞƚƐŬŝ͕/͘^ĂŶĚWZŝŶǀĞƐƟŐĂƟŽŶƐ ŽŶĞīĞĐƚƐŽĨĐŚŽůĞƐƚĞƌŽůĐŽŵƉŽŶĞŶƚŽŶŵŽůĞĐƵůĂƌŝŶƚĞƌĂĐƟŽŶƐďĞƚǁĞĞŶ ƉĂĐůŝƚĂǆĞůĂŶĚƉŚŽƐƉŚŽůŝƉŝĚǁŝƚŚŝŶůŝƉŝĚďŝůĂǇĞƌŵĞŵďƌĂŶĞ͘Int J Pharm ϯϯϴ, ϮϱϴͲϮϲϲ͕ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘ŝũƉŚĂƌŵ͘ϮϬϬϳ͘Ϭϭ͘Ϭϰϱ;ϮϬϬϳͿ͘ ϭϯ ůŽǇ͕:͘K͘ et al. ŽͲůŽĂĚĞĚƉĂĐůŝƚĂǆĞůͬƌĂƉĂŵǇĐŝŶůŝƉŽƐŽŵĞƐ͗ĞǀĞůŽƉŵĞŶƚ͕ ĐŚĂƌĂĐƚĞƌŝǌĂƟŽŶĂŶĚŝŶǀŝƚƌŽĂŶĚŝŶǀŝǀŽĞǀĂůƵĂƟŽŶĨŽƌďƌĞĂƐƚĐĂŶĐĞƌƚŚĞƌĂƉǇ͘

Colloids Surf B Biointerfaces ϭϰϭ͕ϳϰͲϴϮ͕ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘ĐŽůƐƵƌĩ͘ϮϬϭϲ͘Ϭϭ͘ϬϯϮ

;ϮϬϭϲͿ͘

ϭϰ dŽǇƌĂŶ͕E͘Θ^ĞǀĞƌĐĂŶ͕&͘/ŶƚĞƌĂĐƟŽŶďĞƚǁĞĞŶǀŝƚĂŵŝŶϮĂŶĚŵĂŐŶĞƐŝƵŵŝŶ ůŝƉŽƐŽŵĞƐ͗ŝīĞƌĞŶƟĂůƐĐĂŶŶŝŶŐĐĂůŽƌŝŵĞƚƌǇĂŶĚ&d/ZƐƉĞĐƚƌŽƐĐŽƉǇƐƚƵĚŝĞƐ͘

Journal of Molecular Structure ϴϯϵ͕ϭϵͲϮϳ͕ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘ŵŽůƐƚƌƵĐ͘ϮϬϬϲ͘ϭϭ͘ϬϬϱ

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ϭϱ tĂŶŐ͕,͘ et al.'ůŽďĂů͕ƌĞŐŝŽŶĂů͕ĂŶĚŶĂƟŽŶĂůůŝĨĞĞǆƉĞĐƚĂŶĐǇ͕ĂůůͲĐĂƵƐĞ ŵŽƌƚĂůŝƚǇ͕ĂŶĚĐĂƵƐĞͲƐƉĞĐŝĮĐŵŽƌƚĂůŝƚǇĨŽƌϮϰϵĐĂƵƐĞƐŽĨĚĞĂƚŚ͕ϭϵϴϬʹϮϬϭϱ͗Ă ƐǇƐƚĞŵĂƟĐĂŶĂůǇƐŝƐĨŽƌƚŚĞ'ůŽďĂůƵƌĚĞŶŽĨŝƐĞĂƐĞ^ƚƵĚǇϮϬϭϱ͘The Lancet ϯϴϴ͕ϭϰϱϵͲϭϱϰϰ͕ĚŽŝ͗ϭϬ͘ϭϬϭϲͬƐϬϭϰϬͲϲϳϯϲ;ϭϲͿϯϭϬϭϮͲϭ;ϮϬϭϲͿ͘ ϭϲ WŝƌŝůůŽ͕͕͘EŽƌĂƚĂ͕'͘͘ΘĂƚĂƉĂŶŽ͕͘>͘>KyͲϭ͕Kǆ>>͕ĂŶĚĂƚŚĞƌŽƐĐůĞƌŽƐŝƐ͘ DĞĚŝĂƚŽƌƐ/ŶŇĂŵŵ ϮϬϭϯ͕ϭϱϮϳϴϲ͕ĚŽŝ͗ϭϬ͘ϭϭϱϱͬϮϬϭϯͬϭϱϮϳϴϲ;ϮϬϭϯͿ͘ ϭϳ dĂďĂƐ͕/͘Θ>ŝĐŚƚŵĂŶ͕͘,͘DŽŶŽĐǇƚĞͲDĂĐƌŽƉŚĂŐĞƐĂŶĚdĞůůƐŝŶ Atherosclerosis. Immunity ϰϳ͕ϲϮϭͲϲϯϰ͕ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘ŝŵŵƵŶŝ͘ϮϬϭϳ͘Ϭϵ͘ϬϬϴ ;ϮϬϭϳͿ͘

ϭϴ ŽƵŶĂ͕,͘Θ<ƵŝƉĞƌ͕:͘EŽǀĞůͲĐĞůůƐƵďƐĞƚƐŝŶĂƚŚĞƌŽƐĐůĞƌŽƐŝƐ͘Curr Opin Lipidol

Ϯϳ͕ϰϵϯͲϰϵϴ͕ĚŽŝ͗ϭϬ͘ϭϬϵϳͬDK>͘ϬϬϬϬϬϬϬϬϬϬϬϬϬϯϯϱ;ϮϬϭϲͿ͘

ϭϵ dĂůů͕͘Z͘ŚŽůĞƐƚĞƌŽůĞŋƵǆƉĂƚŚǁĂǇƐĂŶĚŽƚŚĞƌƉŽƚĞŶƟĂůŵĞĐŚĂŶŝƐŵƐŝŶǀŽůǀĞĚ ŝŶƚŚĞĂƚŚĞƌŽͲƉƌŽƚĞĐƟǀĞĞīĞĐƚŽĨŚŝŐŚĚĞŶƐŝƚǇůŝƉŽƉƌŽƚĞŝŶƐ͘Journal of Internal

Medicine Ϯϲϯ͕ϮϱϲͲϮϳϯ͕ĚŽŝ͗ϭϬ͘ϭϭϭϭͬũ͘ϭϯϲϱͲϮϳϵϲ͘ϮϬϬϳ͘Ϭϭϴϵϴ͘ǆ;ϮϬϬϴͿ͘

20 Stemme, S. et al.důǇŵƉŚŽĐǇƚĞƐĨƌŽŵŚƵŵĂŶĂƚŚĞƌŽƐĐůĞƌŽƟĐƉůĂƋƵĞƐƌĞĐŽŐŶŝǌĞ ŽǆŝĚŝǌĞĚůŽǁĚĞŶƐŝƚǇůŝƉŽƉƌŽƚĞŝŶ͘Proc Natl Acad Sci U S A ϵϮ, 3893-3897 ;ϭϵϵϱͿ͘

21 Fredrikson, G. N. et al./ĚĞŶƟĮĐĂƟŽŶŽĨŝŵŵƵŶĞƌĞƐƉŽŶƐĞƐĂŐĂŝŶƐƚĂůĚĞŚǇĚĞͲ ŵŽĚŝĮĞĚƉĞƉƟĚĞƐĞƋƵĞŶĐĞƐŝŶĂƉŽĂƐƐŽĐŝĂƚĞĚǁŝƚŚĐĂƌĚŝŽǀĂƐĐƵůĂƌ

disease. Arterioscler Thromb Vasc Biol Ϯϯ͕ϴϳϮͲϴϳϴ͕ĚŽŝ͗ϭϬ͘ϭϭϲϭͬϬϭ͘

ds͘ϬϬϬϬϬϲϳϵϯϱ͘ϬϮϲϳϵ͘Ϭ;ϮϬϬϯͿ͘ ϮϮ ^ũŽŐƌĞŶ͕W͘ et al.,ŝŐŚƉůĂƐŵĂĐŽŶĐĞŶƚƌĂƟŽŶƐŽĨĂƵƚŽĂŶƟďŽĚŝĞƐĂŐĂŝŶƐƚŶĂƟǀĞ ƉĞƉƟĚĞϮϭϬŽĨĂƉŽͲϭϬϬĂƌĞƌĞůĂƚĞĚƚŽůĞƐƐĐŽƌŽŶĂƌǇĂƚŚĞƌŽƐĐůĞƌŽƐŝƐĂŶĚůŽǁĞƌ ƌŝƐŬŽĨŵǇŽĐĂƌĚŝĂůŝŶĨĂƌĐƟŽŶ͘Eur Heart J Ϯϵ͕ϮϮϭϴͲϮϮϮϲ͕ĚŽŝ͗ϭϬ͘ϭϬϵϯͬĞƵƌŚĞĂƌƚũͬ ĞŚŶϯϯϲ;ϮϬϬϴͿ͘ Ϯϯ &ĂŐĞƌďĞƌŐ͕͕͘WƌĂŚů'ƵůůďĞƌŐ͕h͕͘ůŵ͕Z͕͘EŝůƐƐŽŶ͕:͘Θ&ƌĞĚƌŝŬƐŽŶ͕'͘E͘ ŝƌĐƵůĂƟŶŐĂƵƚŽĂŶƟďŽĚŝĞƐĂŐĂŝŶƐƚƚŚĞĂƉŽůŝƉŽƉƌŽƚĞŝŶͲϭϬϬƉĞƉƟĚĞƐƉϰϱĂŶĚ ƉϮϭϬŝŶƌĞůĂƟŽŶƚŽƚŚĞŽĐĐƵƌƌĞŶĐĞŽĨĐĂƌŽƟĚƉůĂƋƵĞƐŝŶϲϰͲǇĞĂƌͲŽůĚǁŽŵĞŶ͘ PLoS One ϭϬ͕ĞϬϭϮϬϳϰϰ͕ĚŽŝ͗ϭϬ͘ϭϯϳϭͬũŽƵƌŶĂů͘ƉŽŶĞ͘ϬϭϮϬϳϰϰ;ϮϬϭϱͿ͘ Ϯϰ ŚŽƵ͕y͕͘ĂůŝŐŝƵƌŝ͕'͕͘,ĂŵƐƚĞŶ͕͕͘>ĞĨǀĞƌƚ͕͘<͘Θ,ĂŶƐƐŽŶ͕'͘<͘>> /ŵŵƵŶŝǌĂƟŽŶ/ŶĚƵĐĞƐdͲĞůůʹĞƉĞŶĚĞŶƚŶƟďŽĚǇ&ŽƌŵĂƟŽŶĂŶĚWƌŽƚĞĐƟŽŶ Against Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology Ϯϭ,

ϭϬϴ;ϮϬϬϭͿ͘

25 Schiopu, A. et al.ZĞĐŽŵďŝŶĂŶƚŚƵŵĂŶĂŶƟďŽĚŝĞƐĂŐĂŝŶƐƚĂůĚĞŚǇĚĞͲŵŽĚŝĮĞĚ ĂƉŽůŝƉŽƉƌŽƚĞŝŶͲϭϬϬƉĞƉƟĚĞƐĞƋƵĞŶĐĞƐŝŶŚŝďŝƚĂƚŚĞƌŽƐĐůĞƌŽƐŝƐ͘ŝƌĐƵůĂƟŽŶ

ϭϭϬ͕ϮϬϰϳͲϮϬϱϮ͕ĚŽŝ͗ϭϬ͘ϭϭϲϭͬϬϭ͘/Z͘ϬϬϬϬϭϰϯϭϲϮ͘ϱϲϬϱϳ͘ϱ;ϮϬϬϰͿ͘

Ϯϲ dƐĞ͕<͘ et al.ƚŚĞƌŽƉƌŽƚĞĐƟǀĞsĂĐĐŝŶĂƟŽŶǁŝƚŚD,Ͳ//ZĞƐƚƌŝĐƚĞĚWĞƉƟĚĞƐĨƌŽŵ ApoB-100. Front Immunol ϰ͕ϰϵϯ͕ĚŽŝ͗ϭϬ͘ϯϯϴϵͬĮŵŵƵ͘ϮϬϭϯ͘ϬϬϰϵϯ;ϮϬϭϯͿ͘

Ϯϳ <ůŝŶŐĞŶďĞƌŐ͕Z͘ et al./ŶƚƌĂŶĂƐĂůŝŵŵƵŶŝǌĂƟŽŶǁŝƚŚĂŶĂƉŽůŝƉŽƉƌŽƚĞŝŶͲϭϬϬ ĨƵƐŝŽŶƉƌŽƚĞŝŶŝŶĚƵĐĞƐĂŶƟŐĞŶͲƐƉĞĐŝĮĐƌĞŐƵůĂƚŽƌǇdĐĞůůƐĂŶĚƌĞĚƵĐĞƐ atherosclerosis. Arterioscler Thromb Vasc Biol ϯϬ͕ϵϰϲͲϵϱϮ͕ĚŽŝ͗ϭϬ͘ϭϭϲϭͬ

ds,͘ϭϬϵ͘ϮϬϮϲϳϭ;ϮϬϭϬͿ͘

28 Herbin, O. et al. Regulatory T-cell response to apolipoprotein B100-derived ƉĞƉƟĚĞƐƌĞĚƵĐĞƐƚŚĞĚĞǀĞůŽƉŵĞŶƚĂŶĚƉƌŽŐƌĞƐƐŝŽŶŽĨĂƚŚĞƌŽƐĐůĞƌŽƐŝƐŝŶŵŝĐĞ͘

Arterioscler Thromb Vasc Biol ϯϮ͕ϲϬϱͲϲϭϮ͕ĚŽŝ͗ϭϬ͘ϭϭϲϭͬds,͘ϭϭϭ͘ϮϰϮϴϬϬ

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7

29 Fredrikson, G. N. et al./ŶŚŝďŝƟŽŶŽĨĂƚŚĞƌŽƐĐůĞƌŽƐŝƐŝŶĂƉŽͲŶƵůůŵŝĐĞďǇ ŝŵŵƵŶŝǌĂƟŽŶǁŝƚŚĂƉŽͲϭϬϬƉĞƉƟĚĞƐĞƋƵĞŶĐĞƐ͘Arterioscler Thromb Vasc Biol

Ϯϯ͕ϴϳϵͲϴϴϰ͕ĚŽŝ͗ϭϬ͘ϭϭϲϭͬϬϭ͘ds͘ϬϬϬϬϬϲϳϵϯϳ͘ϵϯϳϭϲ͘;ϮϬϬϯͿ͘ ϯϬ &ƌĞĚƌŝŬƐŽŶ͕'͘E͕͘ũŽƌŬďĂĐŬĂ͕,͕͘^ŽĚĞƌďĞƌŐ͕/͕͘>ũƵŶŐĐƌĂŶƚǌ͕/͘ΘEŝůƐƐŽŶ͕:͘ dƌĞĂƚŵĞŶƚǁŝƚŚĂƉŽƉĞƉƟĚĞǀĂĐĐŝŶĞƐŝŶŚŝďŝƚƐĂƚŚĞƌŽƐĐůĞƌŽƐŝƐŝŶŚƵŵĂŶ ĂƉŽͲϭϬϬƚƌĂŶƐŐĞŶŝĐŵŝĐĞǁŝƚŚŽƵƚŝŶĚƵĐŝŶŐĂŶŝŶĐƌĞĂƐĞŝŶƉĞƉƟĚĞͲƐƉĞĐŝĮĐ ĂŶƟďŽĚŝĞƐ͘J Intern Med Ϯϲϰ͕ϱϲϯͲϱϳϬ͕ĚŽŝ͗ϭϬ͘ϭϭϭϭͬũ͘ϭϯϲϱͲϮϳϵϲ͘ϮϬϬϴ͘Ϭϭϵϵϱ͘ǆ ;ϮϬϬϴͿ͘ ϯϭ <ŝŵƵƌĂ͕d͘ et al.ZĞŐƵůĂƚŽƌǇϰ;нͿdĞůůƐZĞĐŽŐŶŝǌĞD,Ͳ//ͲZĞƐƚƌŝĐƚĞĚ WĞƉƟĚĞƉŝƚŽƉĞƐŽĨƉŽůŝƉŽƉƌŽƚĞŝŶ͘ŝƌĐƵůĂƟŽŶ ϭϯϴ͕ϭϯ͕ĚŽŝ͗ϭϬ͘ϭϭϲϭͬ /Zh>d/KE,͘ϭϭϳ͘ϬϯϭϰϮϬ;ϮϬϭϴͿ͘ ϯϮ EĂŐĂƚĂ͕^͕͘,ĂŶĂǇĂŵĂ͕Z͘Θ<ĂǁĂŶĞ͕<͘ƵƚŽŝŵŵƵŶŝƚǇĂŶĚƚŚĞĐůĞĂƌĂŶĐĞŽĨ dead cells. Cell ϭϰϬ͕ϲϭϵͲϲϯϬ͕ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘ĐĞůů͘ϮϬϭϬ͘ϬϮ͘Ϭϭϰ;ϮϬϭϬͿ͘

ϯϯ WƵũŽůͲƵƚŽŶĞůů͕/͘ et al.hƐĞŽĨĂƵƚŽĂŶƟŐĞŶͲůŽĂĚĞĚƉŚŽƐƉŚĂƟĚǇůƐĞƌŝŶĞͲ

liposomes to arrest autoimmunity in type 1 diabetes. PLoS One ϭϬ, e0127057,

ĚŽŝ͗ϭϬ͘ϭϯϳϭͬũŽƵƌŶĂů͘ƉŽŶĞ͘ϬϭϮϳϬϱϳ;ϮϬϭϱͿ͘ ϯϰ ZĂŵŽƐ͕'͘͘ et al. ƉŽƉƚŽƟĐŵŝŵŝĐƌǇ͗ƉŚŽƐƉŚĂƟĚǇůƐĞƌŝŶĞůŝƉŽƐŽŵĞƐƌĞĚƵĐĞ ŝŶŇĂŵŵĂƟŽŶƚŚƌŽƵŐŚĂĐƟǀĂƟŽŶŽĨƉĞƌŽǆŝƐŽŵĞƉƌŽůŝĨĞƌĂƚŽƌͲĂĐƟǀĂƚĞĚƌĞĐĞƉƚŽƌƐ ;WWZƐͿŝŶǀŝǀŽ͘ƌŝƟƐŚ:ŽƵƌŶĂůŽĨWŚĂƌŵĂĐŽůŽŐǇ ϭϱϭ͕ϴϰϰͲϴϱϬ͕ĚŽŝ͗ϭϬ͘ϭϬϯϴͬ Ɛũ͘ďũƉ͘ϬϳϬϳϯϬϮ;ϮϬϬϳͿ͘ 35 Ritz, S. et al.WƌŽƚĞŝŶĐŽƌŽŶĂŽĨŶĂŶŽƉĂƌƟĐůĞƐ͗ĚŝƐƟŶĐƚƉƌŽƚĞŝŶƐƌĞŐƵůĂƚĞ the cellular uptake. Biomacromolecules ϭϲ͕ϭϯϭϭͲϭϯϮϭ͕ĚŽŝ͗ϭϬ͘ϭϬϮϭͬĂĐƐ͘

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ϰϰ sĞŶŬĂƚĞƐǁĂƌĂŶ͕͘ et al.ŽŶƚƌŽůŽĨĐĞůůƵůĂƌĐŚŽůĞƐƚĞƌŽůĞŋƵǆďǇƚŚĞŶƵĐůĞĂƌ ŽǆǇƐƚĞƌŽůƌĞĐĞƉƚŽƌ>yZĂůƉŚĂ͘WƌŽĐĞĞĚŝŶŐƐŽĨƚŚĞEĂƟŽŶĂůĐĂĚĞŵǇŽĨ^ĐŝĞŶĐĞƐ

of the United States of America ϵϳ͕ϭϮϬϵϳͲϭϮϭϬϮ͕ĚŽŝ͗ϭϬ͘ϭϬϳϯͬƉŶĂƐ͘ϮϬϬϯϲϳϲϵϳ

;ϮϬϬϬͿ͘

ϰϱ <ŝƌĐŚŐĞƐƐŶĞƌ͕d͘'͘ et al. ĞŶĞĮĐŝĂůĂŶĚĚǀĞƌƐĞīĞĐƚƐŽĨĂŶ>yZŐŽŶŝƐƚŽŶ ,ƵŵĂŶ>ŝƉŝĚĂŶĚ>ŝƉŽƉƌŽƚĞŝŶDĞƚĂďŽůŝƐŵĂŶĚŝƌĐƵůĂƟŶŐEĞƵƚƌŽƉŚŝůƐ͘Cell

Metab Ϯϰ͕ϮϮϯͲϮϯϯ͕ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘ĐŵĞƚ͘ϮϬϭϲ͘Ϭϳ͘Ϭϭϲ;ϮϬϭϲͿ͘

ϰϲ :ŽƐĞƉŚ͕^͘͘ et al.ŝƌĞĐƚĂŶĚŝŶĚŝƌĞĐƚŵĞĐŚĂŶŝƐŵƐĨŽƌƌĞŐƵůĂƟŽŶŽĨĨĂƩǇĂĐŝĚ ƐǇŶƚŚĂƐĞŐĞŶĞĞǆƉƌĞƐƐŝŽŶďǇůŝǀĞƌyƌĞĐĞƉƚŽƌƐ͘J Biol Chem Ϯϳϳ, 11019-11025, ĚŽŝ͗ϭϬ͘ϭϬϳϰͬũďĐ͘DϭϭϭϬϰϭϮϬϬ;ϮϬϬϮͿ͘

ϰϳ :ŽƐĞƉŚ͕^͘͘ et al.^ǇŶƚŚĞƟĐ>yZůŝŐĂŶĚŝŶŚŝďŝƚƐƚŚĞĚĞǀĞůŽƉŵĞŶƚŽĨ

atherosclerosis in mice. Proc Natl Acad Sci U S A ϵϵ͕ϳϲϬϰͲϳϲϬϵ͕ĚŽŝ͗ϭϬ͘ϭϬϳϯͬ

ƉŶĂƐ͘ϭϭϮϬϱϵϮϵϵ;ϮϬϬϮͿ͘

ϰϴ ^ĐŚƵůƚǌ͕:͘Z͘ et al. Role of LXRs in control of lipogenesis. Genes & Development

ϭϰ͕ϮϴϯϭͲϮϴϯϴ͕ĚŽŝ͗ϭϬ͘ϭϭϬϭͬŐĂĚ͘ϴϱϬϰϬϬ;ϮϬϬϬͿ͘

ϰϵ dŝďďŝƩ͕D͘t͕͘ĂŚůŵĂŶ͕:͘͘Θ>ĂŶŐĞƌ͕Z͘ŵĞƌŐŝŶŐ&ƌŽŶƟĞƌƐŝŶƌƵŐĞůŝǀĞƌǇ͘J

Am Chem Soc ϭϯϴ͕ϳϬϰͲϳϭϳ͕ĚŽŝ͗ϭϬ͘ϭϬϮϭͬũĂĐƐ͘ϱďϬϵϵϳϰ;ϮϬϭϲͿ͘

50 Uchida, M. et al. WƌŽƚĞŝŶĐĂŐĞŶĂŶŽƉĂƌƟĐůĞƐďĞĂƌŝŶŐƚŚĞ>ǇWͲϭƉĞƉƟĚĞĨŽƌ enhanced imaging of macrophage-rich vascular lesions. ACS Nano ϱ,

2493-ϮϱϬϮ͕ĚŽŝ͗ϭϬ͘ϭϬϮϭͬŶŶϭϬϮϴϲϯǇ;ϮϬϭϭͿ͘

ϱϭ ^ĞŽ͕:͘t͘ et al.;ϲϰͿƵͲůĂďĞůĞĚ>ǇWͲϭͲĚĞŶĚƌŝŵĞƌĨŽƌWdͲdŝŵĂŐŝŶŐŽĨ

ĂƚŚĞƌŽƐĐůĞƌŽƟĐƉůĂƋƵĞ͘Bioconjug Chem Ϯϱ͕ϮϯϭͲϮϯϵ͕ĚŽŝ͗ϭϬ͘ϭϬϮϭͬďĐϰϬϬϯϰϳƐ ;ϮϬϭϰͿ͘

ϱϮ ^ŝĞŐĞů͕Z͘>͕͘DŝůůĞƌ͕<͘͘Θ:ĞŵĂů͕͘ĂŶĐĞƌƐƚĂƟƐƟĐƐ͕ϮϬϭϵ͘CA Cancer J Clin ϲϵ, ϳͲϯϰ͕ĚŽŝ͗ϭϬ͘ϯϯϮϮͬĐĂĂĐ͘Ϯϭϱϱϭ;ϮϬϭϵͿ͘

ϱϯ ,ĂŶĂŚĂŶ͕͘ΘtĞŝŶďĞƌŐ͕Z͘͘,ĂůůŵĂƌŬƐŽĨĐĂŶĐĞƌ͗ƚŚĞŶĞǆƚŐĞŶĞƌĂƟŽŶ͘Cell

ϭϰϰ͕ϲϰϲͲϲϳϰ͕ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘ĐĞůů͘ϮϬϭϭ͘ϬϮ͘Ϭϭϯ;ϮϬϭϭͿ͘

ϱϰ tŚŝƚĞƐŝĚĞ͕d͘>͘/ŶŚŝďŝƟŶŐƚŚĞŝŶŚŝďŝƚŽƌƐ͗ĞǀĂůƵĂƟŶŐĂŐĞŶƚƐƚĂƌŐĞƟŶŐĐĂŶĐĞƌ immunosuppression. Expert Opin Biol Ther ϭϬ͕ϭϬϭϵͲϭϬϯϱ͕ĚŽŝ͗ϭϬ͘ϭϱϭϳͬϭϰϳϭϮϱ

ϵϴ͘ϮϬϭϬ͘ϰϴϮϮϬϳ;ϮϬϭϬͿ͘ ϱϱ >Ƶ͕z͘͘ΘZŽďďŝŶƐ͕W͘&͘ĂŶĐĞƌŝŵŵƵŶŽƚŚĞƌĂƉǇƚĂƌŐĞƟŶŐŶĞŽĂŶƟŐĞŶƐ͘Semin Immunol Ϯϴ͕ϮϮͲϮϳ͕ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘Ɛŵŝŵ͘ϮϬϭϱ͘ϭϭ͘ϬϬϮ;ϮϬϭϲͿ͘ 56 Nimanong, S. et al.ϰϬ^ŝŐŶĂůŝŶŐƌŝǀĞƐWŽƚĞŶƚĞůůƵůĂƌ/ŵŵƵŶĞ ZĞƐƉŽŶƐĞƐŝŶ,ĞƚĞƌŽůŽŐŽƵƐĂŶĐĞƌsĂĐĐŝŶĂƟŽŶƐ͘Cancer Res ϳϳ, 1918-1926, ĚŽŝ͗ϭϬ͘ϭϭϱϴͬϬϬϬϴͲϱϰϳϮ͘EͲϭϲͲϮϬϴϵ;ϮϬϭϳͿ͘ ϱϳ ŚĞŶ͕W͘ et al.ĞŶĚƌŝƟĐĐĞůůƚĂƌŐĞƚĞĚǀĂĐĐŝŶĞƐ͗ZĞĐĞŶƚƉƌŽŐƌĞƐƐĞƐĂŶĚ

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͘ϭϭϬϱϰϭϱ;ϮϬϭϲͿ͘

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jconrel.2017.05.019;ϮϬϭϳͿ͘ ϲϲ ŶƐĞůŵŽ͕͘͘ΘDŝƚƌĂŐŽƚƌŝ͕^͘EĂŶŽƉĂƌƟĐůĞƐŝŶƚŚĞĐůŝŶŝĐ͘Bioengineering & dƌĂŶƐůĂƟŽŶĂůDĞĚŝĐŝŶĞ ϭ͕ϭϬͲϮϵ͕ĚŽŝ͗ϭϬ͘ϭϬϬϮͬďƚŵϮ͘ϭϬϬϬϯ;ϮϬϭϲͿ͘ ϲϳ ǀĂŶĚĞƌsĂůŬ͕&͘D͘ et al.WƌĞĚŶŝƐŽůŽŶĞͲĐŽŶƚĂŝŶŝŶŐůŝƉŽƐŽŵĞƐĂĐĐƵŵƵůĂƚĞ ŝŶŚƵŵĂŶĂƚŚĞƌŽƐĐůĞƌŽƟĐŵĂĐƌŽƉŚĂŐĞƐƵƉŽŶŝŶƚƌĂǀĞŶŽƵƐĂĚŵŝŶŝƐƚƌĂƟŽŶ͘ Nanomedicine ϭϭ͕ϭϬϯϵͲϭϬϰϲ͕ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘ŶĂŶŽ͘ϮϬϭϱ͘ϬϮ͘ϬϮϭ;ϮϬϭϱͿ͘ 68 Gisterå, A. et al.sĂĐĐŝŶĂƟŽŶĂŐĂŝŶƐƚdͲĐĞůůĞƉŝƚŽƉĞƐŽĨŶĂƟǀĞƉŽϭϬϬ ƌĞĚƵĐĞƐǀĂƐĐƵůĂƌŝŶŇĂŵŵĂƟŽŶĂŶĚĚŝƐĞĂƐĞŝŶĂŚƵŵĂŶŝǌĞĚŵŽƵƐĞŵŽĚĞů of atherosclerosis. Journal of Internal Medicine Ϯϴϭ͕ϯϴϯͲϯϵϳ͕ĚŽŝ͗ϭϬ͘ϭϭϭϭͬ

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ϳϲ ŚĂƚĞŶŽƵĚ͕ >͘ Θ ůƵĞƐƚŽŶĞ͕ :͘ ͘ ϯͲƐƉĞĐŝĮĐ ĂŶƟďŽĚŝĞƐ͗ Ă ƉŽƌƚĂů ƚŽ ƚŚĞ treatment of autoimmunity. Nat Rev Immunol ϳ͕ϲϮϮͲϲϯϮ͕ĚŽŝ͗ϭϬ͘ϭϬϯϴͬŶƌŝϮϭϯϰ

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ĂŶĚŝŶũĞĐƟŽŶĚĞǀŝĐĞƐ͘Chemical Engineering Research and Design ϵϰ, 508-515, doi:ŚƩƉƐ͗ͬͬĚŽŝ͘ŽƌŐͬϭϬ͘ϭϬϭϲͬũ͘ĐŚĞƌĚ͘ϮϬϭϰ͘Ϭϵ͘ϬϬϴ;ϮϬϭϱͿ͘

ϵϭ tĂŐŶĞƌ͕͘ et al.'DWWƌŽĚƵĐƟŽŶŽĨ>ŝƉŽƐŽŵĞƐͶEĞǁ/ŶĚƵƐƚƌŝĂůƉƉƌŽĂĐŚ͘

Journal of Liposome Research ϭϲ͕ϯϭϭͲϯϭϵ͕ĚŽŝ͗ϭϬ͘ϭϬϴϬͬϬϴϵϴϮϭϬϬϲϬϬϴϱϭϬϴϲ

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