NIH grant: Targeted Nanotherapy for Inflammation Resolution, Angiogenesis, and Anti-Fibrosis in Acute Myocardial Infarction (1R01HL187855-01)

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NIH grant 1R01HL187855-01: Targeted Nanotherapy for Inflammation Resolution, Angiogenesis, and Anti-Fibrosis in Acute Myocardial Infarction
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: Jianjun  Guan. Award: $550896.
Start: 2026-08-01T00:00:00.
Program Director/Principal Investigator (Last, First, Middle): GUAN, JIANJUN
 Project Summary
 Following myocardial infarction (MI, or heart attack), the prolonged inflammation arising from a delayed transition
from the proinflammatory phase to the anti-inflammatory phase, extensive cell death within poorly vascularized injury
region, and persistent cardiac fibrosis after myofibroblast formation, progressively deteriorate cardiac function. As
such, it is crucial to timely shift the proinflammatory phase to the anti-inflammatory phase, quickly vascularize the
injured area, and inhibit myofibroblast formation, so as to facilitate the timely repair of the infarcted heart and improve
cardiac function. Despite various therapies explored to treat MI, effective treatment remains a challenge, as current
therapies typically target only one of these three critical aspects. Consequently, their therapeutic efficacy is often
limited. There is a critical need for therapies where a single treatment can simultaneously address all three critical
aspects, and can be quickly and safely administered into weakened hearts as early as possible after MI.
 In this project, we propose a new approach to address the current critical need. We will deliver an engineered
secretome derived from naïve M0 macrophages (M0Mφs), modulated to have upregulated anti-inflammatory,
proangiogenic, and anti-fibrotic factors (proteins and miRNAs), to simultaneously reduce inflammation, promote
angiogenesis, and inhibit myofibroblast formation. To ensure safe and effective delivery of the M0Mφ-secretome into
the infarcted heart during the critical therapeutic window — acute MI stage, we will encapsulate it into nanoparticles
followed by intravenous (IV) administration. This strategy offers a significant advantage over the commonly used direct
myocardial injection, which poses a high risk of rupturing the weakened heart at the acute MI stage. The nanoparticles
will be designed with infarcted heart-targeting, and ROS-scavenging capabilities. Upon IV delivery, they will
preferentially accumulate in the infarcted hearts through vasculature bordering the infarcted area, and leaky
vasculature in the injury area. The nanoparticles will then spatiotemporally release the M0Mφ-secretome and
scavenge upregulated ROS to simultaneously decrease inflammation, promote angiogenesis, and inhibit cardiac
fibrosis.
 We hypothesize that IV delivering, at the acute MI stage, infarcted heart-targeting nanoparticles capable of
releasing M0Mφ-secretome and scavenging ROS, will efficiently decrease tissue inflammation, promote
angiogenesis, and attenuate cardiac fibrosis, leading to a significant increase of cardiac function.
 Aim 1 will engineer M0Mφ-secretome with upregulated anti-inflammatory, proangiogenic and anti-fibrotic factors.
Aim 2 will develop M0Mφ-secretome-releasing, ROS-scavenging, and infarcted heart-targeting nanoparticles. Aim 3
will test efficacy of the developed nanoparticles administered at different times during the acute MI stage.
 This project is innovative because: (1) M0Mφ-secretome has never been applied for MI treatment. For the first
time, we find that M0Mφ-secretome is more effective for cardiac repair after MI than M2Mφ-secretome, despite M2Mφs
are traditionally considered a reparative macrophage subtype; and (2) it develops targeted nanoparticles to rapidly,
safely, and efficiently deliver M0Mφ-secretome during the acute phase of MI, the critical therapeutic window for cardiac
repair.
OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page

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