Photodynamic
therapy (PDT), is a rising star for suppression of in situ and metastatic tumors, yet it is impeded by low
ROS production and off-target phototoxicity. Herein, an aggregation
degree editing strategy, inspired by gene editing, was accomplished
by the coordination of an aggregation degree editor, p(MEO2MA160-co-OEGMA40)-b-pSS30 [POEGS; MEO2MA = 2-(2-methoxyethoxy)ethyl methacrylate, OEGMA = oligo(ethylene
glycol) methacrylate; pSS = poly(styrene sulfonate)]
and indocyanine green (ICG) to nontoxic Mg2+, forming an
ICG discretely loaded nanoaggregate (ICG-DNA). Optimization of the
ICG aggregation degree [POEGS/ICG (P/I) = 6.55] was achieved by tuning
the P/I ratio, alleviating aggregation-caused-quenching (ACQ) and
photobleaching concurrently. The process boosts the PDT efficacy,
spurring robust immunogenic cell death (ICD) and systemic antitumor
immunity against primary and metastatic immunogenic “cold”
4T1 tumors via intratumoral administration. Moreover,
the temperature-sensitive phase-transition property facilitates intratumoral
long-term retention of ICG-DNA, reducing undesired phototoxicity to
normal tissues; meanwhile, the photothermal-induced tumor oxygenation
further leads to an augmented PDT outcome. Thus, this simple strategy
improves PDT efficacy, boosting the singlet oxygen quantum yield (Φ
Δ)-dependent ICD effect and systemic
antitumor responses via local treatment.
p53-targeted microRNAs (miRNAs) markedly affect cellular response to DNA damage. These miRNAs may contribute to either cell cycle arrest or apoptosis induction. However, how these miRNAs coordinate to modulate the decision between cell survival and death remains less understood. Here, we developed an integrated model of p53 signaling network to investigate how p53-targeted miR-192 and miR-22 modulate cellular outcome in response to DNA damage. By numerical simulations, we found that p53 is activated progressively depending on the extent of DNA damage. Upon moderate damage, p53 rises to medium levels and induces miR-192 to promote its own activation, facilitating p21 induction and cell cycle arrest. Upon severe damage, p53 reaches high levels and is fully activated due to phosphatase and tensin homolog (PTEN) induction. As a result, it transactivates miR-22 to repress p21 expression and activate E2F1, resulting in apoptosis. Therefore, miR-192 promotes primary activation of p53, while miR-22 promotes apoptosis by downregulating p21. This work may advance the understanding of the mechanism for cell fate decision between life and death by p53-inducible miRNAs.
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