Nanocarrier-mediated
protein delivery is a promising strategy for
fundamental research and therapeutic applications. However, the efficacy
of the current platforms for delivery into cells is limited by endosomal
entrapment of delivered protein cargo with concomitantly inefficient
access to the cytosol and other organelles, including the nucleus.
We report here a robust, versatile polymeric–protein nanocomposite
(PPNC) platform capable of efficient (≥90%) delivery of proteins
to the cytosol. We synthesized a library of guanidinium-functionalized
poly(oxanorborneneimide) (PONI) homopolymers with varying molecular
weights to stabilize and deliver engineered proteins featuring terminal
oligoglutamate “E-tags”. The polymers were screened
for cytosolic delivery efficiency using imaging flow cytometry with
cytosolic delivery validated using confocal microscopy and activity
of the delivered proteins demonstrated through functional assays.
These studies indicate that the PPNC platform provides highly effective
and tunable cytosolic delivery over a wide range of formulations,
making them robust agents for therapeutic protein delivery.
The delivery of proteins into cells is a potential game changer for a wide array of therapeutic purposes, including cancer therapy, immunomodulation and treatment of inherited diseases. In this review, we present recently developed nanoassemblies for protein delivery that utilize strategies that range from direct assembly, encapsulation and composite formation. We will discuss factors that affect the efficacy of nanoassemblies for delivery from the perspective of both nanoparticles and proteins. Challenges in the field, particularly achieving effective cytosolar protein delivery through endosomal escape or evasion are discussed.
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