The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making KRAS MUT cancers a highly unmet clinical need. Here, we report a class of bottlebrush polyethylene glycol (PEG)–conjugated antisense oligonucleotides (ASOs) for potent in vivo KRAS depletion. Owing to their highly branched architecture, these molecular nanoconstructs suppress nearly all side effects associated with DNA–protein interactions and substantially enhance the pharmacological properties of the ASO, such as plasma pharmacokinetics and tumor uptake. Systemic delivery to mice bearing human non–small-cell lung carcinoma xenografts results in a significant reduction in both KRAS levels and tumor growth, and the antitumor performance well exceeds that of current popular ASO paradigms, such as chemically modified oligonucleotides and PEGylation using linear or slightly branched PEG. Importantly, these conjugates relax the requirement on the ASO chemistry, allowing unmodified, natural phosphodiester ASOs to achieve efficacy comparable to that of chemically modified ones. Both the bottlebrush polymer and its ASO conjugates appear to be safe and well tolerated in mice. Together, these data indicate that the molecular brush–ASO conjugate is a promising therapeutic platform for the treatment of KRAS -driven human cancers and warrant further preclinical and clinical development.
Certain chemotherapeutics can induce tumor cells’ immunogenic cell death (ICD), release tumor antigens, and thereby trigger personalized antitumor immune responses. Co-delivery of adjuvants using nanocarriers could amplify the ICD-induced tumor-specific immunity achieving a synergistic chemo-immunotherapeutic effect. However, complicated preparation, low drug loading efficiency, and potential carrier-associated toxicity are the major challenges that limited its clinical applications. Herein, a carrier-free core–shell nanoparticle (MPLA-CpG-sMMP9-DOX, MCMD NPs) was constructed by facile self-assembly of spherical nucleic acids (SNA) with two adjuvants of CpG ODN and monophosphoryl lipid A (MPLA) as a core and doxorubicin (DOX) radially around the dual-adjuvants SNA as a shell. The results demonstrated that MCMD NPs could enhance drugs accumulation in tumors, and release DOX upon enzymatic degradation of matrix metalloproteinase-9 (MMP-9) peptide in the tumor microenvironment (TME), which enhanced the direct-killing effect of DOX on tumor cells. The core of MPLA-CpG SNA efficiently boosted the ICD-induced antitumor immune response to further attack tumor cells. Thus, MCMD NPs achieved a synergistic therapeutic effect of chemo-immunotherapy with reduced off-target toxicity. This study provided an efficient strategy for the development of a carrier-free nano-delivery system for enhanced cancer chemo-immunotherapy.
Activation of stimulator of interferon genes (STING) can reprogram the immunosuppressive tumor microenvironment (TME) by initiating innate and adaptive immunity. As natural STING agonists, clinical translation of cyclic dinucleotides (CDNs) has been challenged by their short half-life in circulation, poor stability, and low membrane permeability. Herein, we use the natural endogenous small molecules oleic acid and deoxycytidine to construct a ligand for the STING agonist c-di-GMP (CDG), a hydrophobic nucleotide lipid (3′,5′-diOA-dC), which can assemble with CDG into stable cyclic dinucleotide nanoparticles (CDG-NPs) through various supramolecular forces driven by molecular recognition. CDG-NPs are homogeneous and stable spherical nanoparticles with an average diameter of 59.0 ± 13.0 nm. Compared with free CDG, CDG-NPs promote the retention and intracellular delivery of CDG in the tumor site, boost STING activation and TME immunogenicity, and potentiate STING-mediated anti-tumor immunity when administered by either intratumoral or systemic routes in melanoma-bearing mice. We propose a flexible supramolecular nanodelivery system for CDG by using endogenous small molecules, which provides a CDN delivery platform for STING-mediated cancer immunotherapy.
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