PH-responsive lipidoid nanoparticles for intracellular mRNA delivery

A compound of formula I:

• or a pharmaceutically acceptable salt thereof, wherein
• RHead is
• Ra, Ra′, Ra″, and Ra′″ independently are H, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C3-C20 cycloalkyl, C1-C20 heteroalkyl, (heterocyclyl)C1-C20alkyl, aryl, heteroaryl, or
• wherein Ra and Ra′ or Ra″, and Ra′″ are not both
• Z is a C1-C20 bivalent aliphatic radical, a C1-C20 bivalent heteroaliphatic radical, a bivalent aryl radical, or a bivalent heteroaryl radical;
• Linker has a structure represented by formula II:
• wherein
• W is O or NH;
• each of R5 independently is hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocycle, heterocyclyl, aryl, or heteroaryl;
• r is an integer selected from 0 to 4;
• A is an optionally substituted 5- to 8-membered heterocycle;
• R6 is absent;
• or R6 is alkylene or alkenylene;
• each instance of RLipid independently is C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl,
• wherein:
• R1 and R2 independently are H, OH, NHR30, or SH;
• R3 and R4 are both H;
• or R3 and R4 are taken together to form an oxo (═O) group;
• X is CH2, O, NR30, or S;
• R30 is H, C1-6 alkyl, C1-6 alkenyl, or C1-6 alkynyl;
• U and V independently are S, Se, O, or CH2;
• m is an integer selected from 1 to 3;
• n is an integer selected from 1 to 14;
• p is 0 or 1;
• q is an integer selected from 1 to 10;
• and
• t is 0, 1, or 2.